the highs and lows of genetic prediction highs and... · the highs and lows of genetic prediction...
TRANSCRIPT
The highs and lows of genetic prediction
Sir John Burn MD
FRCP FRCPE FRCPCH FRCOG FMedSci Professor of Clinical Genetics Newcastle University UK
Institute of Genetic Medicine Newcastle University UK
Oxford September 15th 2014
CCG U C A G
U C A G
UCAG
Phe Phe Leu Leu
Ser Ser Ser Ser
Tyr Tyr STOP STOP
Cys Cys STOP Trp
Leu Leu Leu Leu
Pro Pro Pro Pro
His His Gln Gln
Arg Arg Arg Arg
Ile Ile Ile Met
Val Val Val Val
Thr Thr Thr Thr
Asn Asn Lys Lys
Ala Ala Ala Ala
Asp Asp Glu Glu
Ser Ser Arg Arg
Gly Gly Gly Gly
UCAG
UCAG
UCAG
lsquohereditaryrsquo tumour 2 hit hypothesis
predisposed tumour
Retinoblastoma loss of Rb on 13
Family at risk of breast cancer due to p53 mutation
Breast Cancer
bull 4 high penetrance genes
ndash BRCA1 breastovarian
ndash BRCA2 breastovarian
ndash P53 breast+sarcoma+others
ndash PTEN breast + thyroid+overgrowth
I1 I2
55
II2
49
II1 II3
45
For individual III1Calculated risk of cancer (20Heterozygote risk 190
10 year risk 0920 year risk 4430 year risk 97
Lifetime risk (85) 243
familial breast cancer
Individual III 1 at 20
Heterozygote 19
10 year risk 09
20 year risk 44
30 year risk 97
Lifetime risk 24
PARP inhibitors mechanism
DNA DSB
ATMR
ERCC1 XRCC3
NBS1 MRE11
Rad50 BRCA1
gH2AX
HR repair
DNA SSB
DNA replication
BER PARP
XRCC1
Pol Lig III
FA core complex FANC
D2
Rad 524 RPA
Rad 51 BRCA2
bull Endogenously formed SSB are normally repaired by PARP-dependent BER
bull If PARP is inhibited SSB persist
bull SSB form DSB at replication which are repaired by HR
bull If HR is defective the breaks are not repaired and the cell dies
bull This is the first exploitation of synthetic lethality in cancer therapy
Lynch syndrome
Endometrial
Carcinoma
Bertha
Ted
3 CRC
9 skin
cancers
Family from which DNA used to Demonstrate hMSH2 mutation by Kolodnerrsquos group 1993 1st of the MISMATCH REPAIR GENE DEFECTS
Muir Torre syndrome A sub type of Lynch syndrome
ndash Microsatellites are lengths of short repeated sequences usually
ndash mononucleotides eg BAT25
tgttttgtttttttgatttttttttttttttttttttttttgagaacagagca
ndash or dinucleotides eg D5S346
aatttacacacacacacacacacacacacacacagagta
Microsatellites
600mg aspirinday for 2 yrs reduced Lynch syndrome cancers at 5 yrs
by over 50
Lancet volume 378 December 11th 2011
CAPP2 follow up data May 2013
30
10
40
20
45434
25427
12 years New colorectal cancers in blinded recruits treated for mean 25 yrs with 600mg Aspirin (green) or placebo (red) Unpublished data
= Washington University
Genome Sequencing Center
Baylor College of Medicine
Human Genome Sequencing Center
Using AB 3730 XL
fluorescent Sanger chemistry
on capillary sequencers
per month
Sequencing 2005
Next-generation sequencers
Slide courtesy of
John D McPherson OICR
Sequencing Now
First woman sequenced June 2008
Human amp Clinical Genetics
Marjolein Kriek PhD clinical geneticist
34
ldquoMan takes one step towards understanding womanrdquo
Human Genomics Strategy Group bull Government response
ndash 100000 whole genomes ndash pound100 million investment ndash Genomics Strategy Board
(NHS now HEE)
Newcastle one of four pilot centres 209743 rare disease samples (130114)
3 million
Error rates inadequate depth of coverage
copy number variation imprinted genes
splice variants
W hole genome sequencing
Functional classification of JDW SNPs
SNP Type Known SNPs Novel SNPs
Missense 8967 2421
Nonsense 44 5
Synonymous 9121 2261
UTR 18517 7102
Intron 922048 381924
August 2010 China National Highway 110 traffic jam China worldrsquos worst
traffic jam everhellip
more than 100 kilometres from August 14 - 26 inc at least 11 days of total
gridlock
We are heading for the biggest traffic jam in history
Hereditary colorectal cancer Should I request colonoscopy
Donna-Marie Ian
25 24
Positive FH
MSI high tumour
MLH1 leu559arg
Missense
Not inherited
Robert Hofstra
Rolf Sijmons
Westernno expression
Pulldown no interaction
MAPP-MMR and SIFT v2
Suggest pathogenic
Polyphen inconclusive
Reported Belvederesi EJHG
2006
Grantham Variation (GV) and Deviation (GD)
C
P
V Grantham R Science 185 862-864 1974
Tavtigian et al JMG 43 295 2006
GV
GD
HVP4 UNESCO Headquarters Paris 11-15 June 2012
Estimates of Heritability
Disorder Frequency () ()
bull Schizophrenia 1 85
bull Asthma 4 80
bull Ankylosing spondylitis 02 70
bull Neural tube defects 02 60
bull Congenital heart disease 05 60
21
bull Paper by Galton
ldquoChildren regress to
Mediocrityrdquo
Imagine if there were only 2 genes for height each with only 2 alleles H or T of equal
frequency
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
10
We discover one of the genes and call it BYH1 somebody would suggest using it for disease
prediction
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
average short Very
short tall
Very
tall
Always bump
your head
Often bump
Your head
ldquohundreds of variants in at least 180 loci influence human heightrdquo
Nature 2010 Oct 14467(7317)832-8 doi 101038nature09410 Epub 2010 Sep 29 Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen H1 Estrada K Lettre G Berndt SI Weedon MN Rivadeneira F Willer CJ Jackson AU Vedantam S Raychaudhuri S Ferreira T Wood AR Weyant RJ Segregrave AV Speliotes EK Wheeler E Soranzo N Park JH Yang J Gudbjartsson D Heard-Costa NL Randall JC Qi L Vernon Smith A Maumlgi R Pastinen T Liang L Heid IM Luan J Thorleifsson G Winkler TW Goddard ME Sin Lo K Palmer C Workalemahu T Aulchenko YS Johansson A Zillikens MC Feitosa MF Esko T Johnson T Ketkar S Kraft P Mangino M Prokopenko I Absher D Albrecht E Ernst F Glazer NL Hayward C Hottenga JJ Jacobs KB Knowles JW Kutalik Z Monda KL Polasek O Preuss M Rayner NW Robertson NR Steinthorsdottir V Tyrer JP Voight BF Wiklund F Xu J Zhao JH Nyholt DR Pellikka N Perola M Perry JR Surakka I Tammesoo ML Altmaier EL Amin N Aspelund T Bhangale T Boucher G Chasman DI Chen C Coin L Cooper MN Dixon AL Gibson Q Grundberg E Hao K Juhani Junttila M Kaplan LM Kettunen J Koumlnig IR Kwan T Lawrence RW Levinson DF Lorentzon M McKnight B Morris AP Muumlller M Suh Ngwa J Purcell S Rafelt S Salem RM Salvi E Sanna S Shi J Sovio U Thompson JR Turchin MC Vandenput L Verlaan DJ Vitart V White CC Ziegler A Almgren P Balmforth AJ Campbell H Citterio L De Grandi A Dominiczak A Duan J Elliott P Elosua R Eriksson JG Freimer NB Geus EJ Glorioso N Haiqing S Hartikainen AL Havulinna AS Hicks AA Hui J Igl W Illig T Jula A Kajantie E Kilpelaumlinen TO Koiranen M Kolcic I Koskinen S Kovacs P Laitinen J Liu J Lokki ML Marusic A Maschio A Meitinger T Mulas A Pareacute G Parker AN Peden JF Petersmann A Pichler I Pietilaumlinen KH Pouta A Ridderstraringle M Rotter JI Sambrook JG Sanders AR Schmidt CO Sinisalo J Smit JH Stringham HM Bragi Walters G Widen E Wild SH Willemsen G Zagato L Zgaga L Zitting P Alavere H Farrall M McArdle WL Nelis M Peters MJ Ripatti S van Meurs JB Aben KK Ardlie KG Beckmann JS Beilby JP Bergman RN Bergmann S Collins FS Cusi D den Heijer M Eiriksdottir G Gejman PV Hall AS Hamsten A Huikuri HV Iribarren C Kaumlhoumlnen M Kaprio J Kathiresan S Kiemeney L Kocher T Launer LJ Lehtimaumlki T Melander O Mosley TH Jr Musk AW Nieminen MS ODonnell CJ Ohlsson C Oostra B Palmer LJ Raitakari O Ridker PM Rioux JD Rissanen A Rivolta C Schunkert H Shuldiner AR Siscovick DS Stumvoll M Toumlnjes A Tuomilehto J van Ommen GJ Viikari J Heath AC Martin NG Montgomery GW Province MA Kayser M Arnold AM Atwood LD Boerwinkle E Chanock SJ Deloukas P Gieger C Groumlnberg H Hall P Hattersley AT Hengstenberg C Hoffman W Lathrop GM Salomaa V Schreiber S Uda M Waterworth D Wright AF Assimes TL Barroso I Hofman A Mohlke KL Boomsma DI Caulfield MJ Cupples LA Erdmann J Fox CS Gudnason V Gyllensten U Harris TB Hayes RB Jarvelin MR Mooser V Munroe PB Ouwehand WH Penninx BW Pramstaller PP Quertermous T Rudan I Samani NJ Spector TD Voumllzke H Watkins H Wilson JF Groop LC Haritunians T Hu FB Kaplan RC Metspalu A North KE Schlessinger D Wareham NJ Hunter DJ OConnell JR Strachan DP Wichmann HE Borecki IB van Duijn CM Schadt EE Thorsteinsdottir U Peltonen L Uitterlinden AG Visscher PM Chatterjee N Loos RJ Boehnke M McCarthy MI Ingelsson E Lindgren CM Abecasis GR Stefansson K Frayling TM Hirschhorn JN
Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen et alNature 2010 Oct 14467(7317)832-8
RISK SCORE METHOD
PROCAMFramingham Classical Risk factors
0
025
05
075
1
10 105 11 115 12 125 13 135
Risk Score
Pro
ba
bil
ity
no CHD CHD Set Specificity at
5 False Positive
in no-CAD
11 of men who get
CAD have baseline
score over cut-off
89 of the events that occurred over 10 years
would not be predicted by the score
Can we improve on this with genotypes
Whıch genes
to study
20
Genotype - smoking interactions
in risk score
Better than classical +
genotypes plt00001
Adding Environment-Genotype interactions
enhances (DOUBLES) risk prediction score
0
02
04
06
6 7 8 9 10 11 12
Risk score
pro
bab
ilit
y
no CHD CHD
EVEN BETTER
24 of cases
have score
over cut-off
5 FPR
Classical Risk factors + Genotypes + Smokıng
22
2001
Cui Y Wei QQ Park HK amp Lieber CM Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species Science 293 1289ndash1292 (2001)
ldquoDevices based on nanowires are emerging as a powerful platform for the direct detection of biological and chemical species including low concentrations of proteins and virusesrdquo 1st July 2006 Analytic Chemistry
No
rma
lise
d
con
du
ctan
ce c
han
ge
Figure 18 | taken from E Stern JF Klemic DA Routenberg PN Wyrembak DB
Turner-Evans AD Hamilton DA LaVan TM Fahmy and MA Reed Label-free
immunodetection with CMOS-compatible semiconducting nanowires Nature 445
05498 (2007)
Born April 2014
Nanowire chip
DNA extraction
PCR
ldquoHandheldrdquo
Arrived from the engineers at A Star Singapore LAST WEEK
First cassettes Chloroquine resistant Malaria warfarin BRAF
tumour marker
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated
CCG U C A G
U C A G
UCAG
Phe Phe Leu Leu
Ser Ser Ser Ser
Tyr Tyr STOP STOP
Cys Cys STOP Trp
Leu Leu Leu Leu
Pro Pro Pro Pro
His His Gln Gln
Arg Arg Arg Arg
Ile Ile Ile Met
Val Val Val Val
Thr Thr Thr Thr
Asn Asn Lys Lys
Ala Ala Ala Ala
Asp Asp Glu Glu
Ser Ser Arg Arg
Gly Gly Gly Gly
UCAG
UCAG
UCAG
lsquohereditaryrsquo tumour 2 hit hypothesis
predisposed tumour
Retinoblastoma loss of Rb on 13
Family at risk of breast cancer due to p53 mutation
Breast Cancer
bull 4 high penetrance genes
ndash BRCA1 breastovarian
ndash BRCA2 breastovarian
ndash P53 breast+sarcoma+others
ndash PTEN breast + thyroid+overgrowth
I1 I2
55
II2
49
II1 II3
45
For individual III1Calculated risk of cancer (20Heterozygote risk 190
10 year risk 0920 year risk 4430 year risk 97
Lifetime risk (85) 243
familial breast cancer
Individual III 1 at 20
Heterozygote 19
10 year risk 09
20 year risk 44
30 year risk 97
Lifetime risk 24
PARP inhibitors mechanism
DNA DSB
ATMR
ERCC1 XRCC3
NBS1 MRE11
Rad50 BRCA1
gH2AX
HR repair
DNA SSB
DNA replication
BER PARP
XRCC1
Pol Lig III
FA core complex FANC
D2
Rad 524 RPA
Rad 51 BRCA2
bull Endogenously formed SSB are normally repaired by PARP-dependent BER
bull If PARP is inhibited SSB persist
bull SSB form DSB at replication which are repaired by HR
bull If HR is defective the breaks are not repaired and the cell dies
bull This is the first exploitation of synthetic lethality in cancer therapy
Lynch syndrome
Endometrial
Carcinoma
Bertha
Ted
3 CRC
9 skin
cancers
Family from which DNA used to Demonstrate hMSH2 mutation by Kolodnerrsquos group 1993 1st of the MISMATCH REPAIR GENE DEFECTS
Muir Torre syndrome A sub type of Lynch syndrome
ndash Microsatellites are lengths of short repeated sequences usually
ndash mononucleotides eg BAT25
tgttttgtttttttgatttttttttttttttttttttttttgagaacagagca
ndash or dinucleotides eg D5S346
aatttacacacacacacacacacacacacacacagagta
Microsatellites
600mg aspirinday for 2 yrs reduced Lynch syndrome cancers at 5 yrs
by over 50
Lancet volume 378 December 11th 2011
CAPP2 follow up data May 2013
30
10
40
20
45434
25427
12 years New colorectal cancers in blinded recruits treated for mean 25 yrs with 600mg Aspirin (green) or placebo (red) Unpublished data
= Washington University
Genome Sequencing Center
Baylor College of Medicine
Human Genome Sequencing Center
Using AB 3730 XL
fluorescent Sanger chemistry
on capillary sequencers
per month
Sequencing 2005
Next-generation sequencers
Slide courtesy of
John D McPherson OICR
Sequencing Now
First woman sequenced June 2008
Human amp Clinical Genetics
Marjolein Kriek PhD clinical geneticist
34
ldquoMan takes one step towards understanding womanrdquo
Human Genomics Strategy Group bull Government response
ndash 100000 whole genomes ndash pound100 million investment ndash Genomics Strategy Board
(NHS now HEE)
Newcastle one of four pilot centres 209743 rare disease samples (130114)
3 million
Error rates inadequate depth of coverage
copy number variation imprinted genes
splice variants
W hole genome sequencing
Functional classification of JDW SNPs
SNP Type Known SNPs Novel SNPs
Missense 8967 2421
Nonsense 44 5
Synonymous 9121 2261
UTR 18517 7102
Intron 922048 381924
August 2010 China National Highway 110 traffic jam China worldrsquos worst
traffic jam everhellip
more than 100 kilometres from August 14 - 26 inc at least 11 days of total
gridlock
We are heading for the biggest traffic jam in history
Hereditary colorectal cancer Should I request colonoscopy
Donna-Marie Ian
25 24
Positive FH
MSI high tumour
MLH1 leu559arg
Missense
Not inherited
Robert Hofstra
Rolf Sijmons
Westernno expression
Pulldown no interaction
MAPP-MMR and SIFT v2
Suggest pathogenic
Polyphen inconclusive
Reported Belvederesi EJHG
2006
Grantham Variation (GV) and Deviation (GD)
C
P
V Grantham R Science 185 862-864 1974
Tavtigian et al JMG 43 295 2006
GV
GD
HVP4 UNESCO Headquarters Paris 11-15 June 2012
Estimates of Heritability
Disorder Frequency () ()
bull Schizophrenia 1 85
bull Asthma 4 80
bull Ankylosing spondylitis 02 70
bull Neural tube defects 02 60
bull Congenital heart disease 05 60
21
bull Paper by Galton
ldquoChildren regress to
Mediocrityrdquo
Imagine if there were only 2 genes for height each with only 2 alleles H or T of equal
frequency
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
10
We discover one of the genes and call it BYH1 somebody would suggest using it for disease
prediction
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
average short Very
short tall
Very
tall
Always bump
your head
Often bump
Your head
ldquohundreds of variants in at least 180 loci influence human heightrdquo
Nature 2010 Oct 14467(7317)832-8 doi 101038nature09410 Epub 2010 Sep 29 Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen H1 Estrada K Lettre G Berndt SI Weedon MN Rivadeneira F Willer CJ Jackson AU Vedantam S Raychaudhuri S Ferreira T Wood AR Weyant RJ Segregrave AV Speliotes EK Wheeler E Soranzo N Park JH Yang J Gudbjartsson D Heard-Costa NL Randall JC Qi L Vernon Smith A Maumlgi R Pastinen T Liang L Heid IM Luan J Thorleifsson G Winkler TW Goddard ME Sin Lo K Palmer C Workalemahu T Aulchenko YS Johansson A Zillikens MC Feitosa MF Esko T Johnson T Ketkar S Kraft P Mangino M Prokopenko I Absher D Albrecht E Ernst F Glazer NL Hayward C Hottenga JJ Jacobs KB Knowles JW Kutalik Z Monda KL Polasek O Preuss M Rayner NW Robertson NR Steinthorsdottir V Tyrer JP Voight BF Wiklund F Xu J Zhao JH Nyholt DR Pellikka N Perola M Perry JR Surakka I Tammesoo ML Altmaier EL Amin N Aspelund T Bhangale T Boucher G Chasman DI Chen C Coin L Cooper MN Dixon AL Gibson Q Grundberg E Hao K Juhani Junttila M Kaplan LM Kettunen J Koumlnig IR Kwan T Lawrence RW Levinson DF Lorentzon M McKnight B Morris AP Muumlller M Suh Ngwa J Purcell S Rafelt S Salem RM Salvi E Sanna S Shi J Sovio U Thompson JR Turchin MC Vandenput L Verlaan DJ Vitart V White CC Ziegler A Almgren P Balmforth AJ Campbell H Citterio L De Grandi A Dominiczak A Duan J Elliott P Elosua R Eriksson JG Freimer NB Geus EJ Glorioso N Haiqing S Hartikainen AL Havulinna AS Hicks AA Hui J Igl W Illig T Jula A Kajantie E Kilpelaumlinen TO Koiranen M Kolcic I Koskinen S Kovacs P Laitinen J Liu J Lokki ML Marusic A Maschio A Meitinger T Mulas A Pareacute G Parker AN Peden JF Petersmann A Pichler I Pietilaumlinen KH Pouta A Ridderstraringle M Rotter JI Sambrook JG Sanders AR Schmidt CO Sinisalo J Smit JH Stringham HM Bragi Walters G Widen E Wild SH Willemsen G Zagato L Zgaga L Zitting P Alavere H Farrall M McArdle WL Nelis M Peters MJ Ripatti S van Meurs JB Aben KK Ardlie KG Beckmann JS Beilby JP Bergman RN Bergmann S Collins FS Cusi D den Heijer M Eiriksdottir G Gejman PV Hall AS Hamsten A Huikuri HV Iribarren C Kaumlhoumlnen M Kaprio J Kathiresan S Kiemeney L Kocher T Launer LJ Lehtimaumlki T Melander O Mosley TH Jr Musk AW Nieminen MS ODonnell CJ Ohlsson C Oostra B Palmer LJ Raitakari O Ridker PM Rioux JD Rissanen A Rivolta C Schunkert H Shuldiner AR Siscovick DS Stumvoll M Toumlnjes A Tuomilehto J van Ommen GJ Viikari J Heath AC Martin NG Montgomery GW Province MA Kayser M Arnold AM Atwood LD Boerwinkle E Chanock SJ Deloukas P Gieger C Groumlnberg H Hall P Hattersley AT Hengstenberg C Hoffman W Lathrop GM Salomaa V Schreiber S Uda M Waterworth D Wright AF Assimes TL Barroso I Hofman A Mohlke KL Boomsma DI Caulfield MJ Cupples LA Erdmann J Fox CS Gudnason V Gyllensten U Harris TB Hayes RB Jarvelin MR Mooser V Munroe PB Ouwehand WH Penninx BW Pramstaller PP Quertermous T Rudan I Samani NJ Spector TD Voumllzke H Watkins H Wilson JF Groop LC Haritunians T Hu FB Kaplan RC Metspalu A North KE Schlessinger D Wareham NJ Hunter DJ OConnell JR Strachan DP Wichmann HE Borecki IB van Duijn CM Schadt EE Thorsteinsdottir U Peltonen L Uitterlinden AG Visscher PM Chatterjee N Loos RJ Boehnke M McCarthy MI Ingelsson E Lindgren CM Abecasis GR Stefansson K Frayling TM Hirschhorn JN
Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen et alNature 2010 Oct 14467(7317)832-8
RISK SCORE METHOD
PROCAMFramingham Classical Risk factors
0
025
05
075
1
10 105 11 115 12 125 13 135
Risk Score
Pro
ba
bil
ity
no CHD CHD Set Specificity at
5 False Positive
in no-CAD
11 of men who get
CAD have baseline
score over cut-off
89 of the events that occurred over 10 years
would not be predicted by the score
Can we improve on this with genotypes
Whıch genes
to study
20
Genotype - smoking interactions
in risk score
Better than classical +
genotypes plt00001
Adding Environment-Genotype interactions
enhances (DOUBLES) risk prediction score
0
02
04
06
6 7 8 9 10 11 12
Risk score
pro
bab
ilit
y
no CHD CHD
EVEN BETTER
24 of cases
have score
over cut-off
5 FPR
Classical Risk factors + Genotypes + Smokıng
22
2001
Cui Y Wei QQ Park HK amp Lieber CM Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species Science 293 1289ndash1292 (2001)
ldquoDevices based on nanowires are emerging as a powerful platform for the direct detection of biological and chemical species including low concentrations of proteins and virusesrdquo 1st July 2006 Analytic Chemistry
No
rma
lise
d
con
du
ctan
ce c
han
ge
Figure 18 | taken from E Stern JF Klemic DA Routenberg PN Wyrembak DB
Turner-Evans AD Hamilton DA LaVan TM Fahmy and MA Reed Label-free
immunodetection with CMOS-compatible semiconducting nanowires Nature 445
05498 (2007)
Born April 2014
Nanowire chip
DNA extraction
PCR
ldquoHandheldrdquo
Arrived from the engineers at A Star Singapore LAST WEEK
First cassettes Chloroquine resistant Malaria warfarin BRAF
tumour marker
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated
lsquohereditaryrsquo tumour 2 hit hypothesis
predisposed tumour
Retinoblastoma loss of Rb on 13
Family at risk of breast cancer due to p53 mutation
Breast Cancer
bull 4 high penetrance genes
ndash BRCA1 breastovarian
ndash BRCA2 breastovarian
ndash P53 breast+sarcoma+others
ndash PTEN breast + thyroid+overgrowth
I1 I2
55
II2
49
II1 II3
45
For individual III1Calculated risk of cancer (20Heterozygote risk 190
10 year risk 0920 year risk 4430 year risk 97
Lifetime risk (85) 243
familial breast cancer
Individual III 1 at 20
Heterozygote 19
10 year risk 09
20 year risk 44
30 year risk 97
Lifetime risk 24
PARP inhibitors mechanism
DNA DSB
ATMR
ERCC1 XRCC3
NBS1 MRE11
Rad50 BRCA1
gH2AX
HR repair
DNA SSB
DNA replication
BER PARP
XRCC1
Pol Lig III
FA core complex FANC
D2
Rad 524 RPA
Rad 51 BRCA2
bull Endogenously formed SSB are normally repaired by PARP-dependent BER
bull If PARP is inhibited SSB persist
bull SSB form DSB at replication which are repaired by HR
bull If HR is defective the breaks are not repaired and the cell dies
bull This is the first exploitation of synthetic lethality in cancer therapy
Lynch syndrome
Endometrial
Carcinoma
Bertha
Ted
3 CRC
9 skin
cancers
Family from which DNA used to Demonstrate hMSH2 mutation by Kolodnerrsquos group 1993 1st of the MISMATCH REPAIR GENE DEFECTS
Muir Torre syndrome A sub type of Lynch syndrome
ndash Microsatellites are lengths of short repeated sequences usually
ndash mononucleotides eg BAT25
tgttttgtttttttgatttttttttttttttttttttttttgagaacagagca
ndash or dinucleotides eg D5S346
aatttacacacacacacacacacacacacacacagagta
Microsatellites
600mg aspirinday for 2 yrs reduced Lynch syndrome cancers at 5 yrs
by over 50
Lancet volume 378 December 11th 2011
CAPP2 follow up data May 2013
30
10
40
20
45434
25427
12 years New colorectal cancers in blinded recruits treated for mean 25 yrs with 600mg Aspirin (green) or placebo (red) Unpublished data
= Washington University
Genome Sequencing Center
Baylor College of Medicine
Human Genome Sequencing Center
Using AB 3730 XL
fluorescent Sanger chemistry
on capillary sequencers
per month
Sequencing 2005
Next-generation sequencers
Slide courtesy of
John D McPherson OICR
Sequencing Now
First woman sequenced June 2008
Human amp Clinical Genetics
Marjolein Kriek PhD clinical geneticist
34
ldquoMan takes one step towards understanding womanrdquo
Human Genomics Strategy Group bull Government response
ndash 100000 whole genomes ndash pound100 million investment ndash Genomics Strategy Board
(NHS now HEE)
Newcastle one of four pilot centres 209743 rare disease samples (130114)
3 million
Error rates inadequate depth of coverage
copy number variation imprinted genes
splice variants
W hole genome sequencing
Functional classification of JDW SNPs
SNP Type Known SNPs Novel SNPs
Missense 8967 2421
Nonsense 44 5
Synonymous 9121 2261
UTR 18517 7102
Intron 922048 381924
August 2010 China National Highway 110 traffic jam China worldrsquos worst
traffic jam everhellip
more than 100 kilometres from August 14 - 26 inc at least 11 days of total
gridlock
We are heading for the biggest traffic jam in history
Hereditary colorectal cancer Should I request colonoscopy
Donna-Marie Ian
25 24
Positive FH
MSI high tumour
MLH1 leu559arg
Missense
Not inherited
Robert Hofstra
Rolf Sijmons
Westernno expression
Pulldown no interaction
MAPP-MMR and SIFT v2
Suggest pathogenic
Polyphen inconclusive
Reported Belvederesi EJHG
2006
Grantham Variation (GV) and Deviation (GD)
C
P
V Grantham R Science 185 862-864 1974
Tavtigian et al JMG 43 295 2006
GV
GD
HVP4 UNESCO Headquarters Paris 11-15 June 2012
Estimates of Heritability
Disorder Frequency () ()
bull Schizophrenia 1 85
bull Asthma 4 80
bull Ankylosing spondylitis 02 70
bull Neural tube defects 02 60
bull Congenital heart disease 05 60
21
bull Paper by Galton
ldquoChildren regress to
Mediocrityrdquo
Imagine if there were only 2 genes for height each with only 2 alleles H or T of equal
frequency
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
10
We discover one of the genes and call it BYH1 somebody would suggest using it for disease
prediction
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
average short Very
short tall
Very
tall
Always bump
your head
Often bump
Your head
ldquohundreds of variants in at least 180 loci influence human heightrdquo
Nature 2010 Oct 14467(7317)832-8 doi 101038nature09410 Epub 2010 Sep 29 Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen H1 Estrada K Lettre G Berndt SI Weedon MN Rivadeneira F Willer CJ Jackson AU Vedantam S Raychaudhuri S Ferreira T Wood AR Weyant RJ Segregrave AV Speliotes EK Wheeler E Soranzo N Park JH Yang J Gudbjartsson D Heard-Costa NL Randall JC Qi L Vernon Smith A Maumlgi R Pastinen T Liang L Heid IM Luan J Thorleifsson G Winkler TW Goddard ME Sin Lo K Palmer C Workalemahu T Aulchenko YS Johansson A Zillikens MC Feitosa MF Esko T Johnson T Ketkar S Kraft P Mangino M Prokopenko I Absher D Albrecht E Ernst F Glazer NL Hayward C Hottenga JJ Jacobs KB Knowles JW Kutalik Z Monda KL Polasek O Preuss M Rayner NW Robertson NR Steinthorsdottir V Tyrer JP Voight BF Wiklund F Xu J Zhao JH Nyholt DR Pellikka N Perola M Perry JR Surakka I Tammesoo ML Altmaier EL Amin N Aspelund T Bhangale T Boucher G Chasman DI Chen C Coin L Cooper MN Dixon AL Gibson Q Grundberg E Hao K Juhani Junttila M Kaplan LM Kettunen J Koumlnig IR Kwan T Lawrence RW Levinson DF Lorentzon M McKnight B Morris AP Muumlller M Suh Ngwa J Purcell S Rafelt S Salem RM Salvi E Sanna S Shi J Sovio U Thompson JR Turchin MC Vandenput L Verlaan DJ Vitart V White CC Ziegler A Almgren P Balmforth AJ Campbell H Citterio L De Grandi A Dominiczak A Duan J Elliott P Elosua R Eriksson JG Freimer NB Geus EJ Glorioso N Haiqing S Hartikainen AL Havulinna AS Hicks AA Hui J Igl W Illig T Jula A Kajantie E Kilpelaumlinen TO Koiranen M Kolcic I Koskinen S Kovacs P Laitinen J Liu J Lokki ML Marusic A Maschio A Meitinger T Mulas A Pareacute G Parker AN Peden JF Petersmann A Pichler I Pietilaumlinen KH Pouta A Ridderstraringle M Rotter JI Sambrook JG Sanders AR Schmidt CO Sinisalo J Smit JH Stringham HM Bragi Walters G Widen E Wild SH Willemsen G Zagato L Zgaga L Zitting P Alavere H Farrall M McArdle WL Nelis M Peters MJ Ripatti S van Meurs JB Aben KK Ardlie KG Beckmann JS Beilby JP Bergman RN Bergmann S Collins FS Cusi D den Heijer M Eiriksdottir G Gejman PV Hall AS Hamsten A Huikuri HV Iribarren C Kaumlhoumlnen M Kaprio J Kathiresan S Kiemeney L Kocher T Launer LJ Lehtimaumlki T Melander O Mosley TH Jr Musk AW Nieminen MS ODonnell CJ Ohlsson C Oostra B Palmer LJ Raitakari O Ridker PM Rioux JD Rissanen A Rivolta C Schunkert H Shuldiner AR Siscovick DS Stumvoll M Toumlnjes A Tuomilehto J van Ommen GJ Viikari J Heath AC Martin NG Montgomery GW Province MA Kayser M Arnold AM Atwood LD Boerwinkle E Chanock SJ Deloukas P Gieger C Groumlnberg H Hall P Hattersley AT Hengstenberg C Hoffman W Lathrop GM Salomaa V Schreiber S Uda M Waterworth D Wright AF Assimes TL Barroso I Hofman A Mohlke KL Boomsma DI Caulfield MJ Cupples LA Erdmann J Fox CS Gudnason V Gyllensten U Harris TB Hayes RB Jarvelin MR Mooser V Munroe PB Ouwehand WH Penninx BW Pramstaller PP Quertermous T Rudan I Samani NJ Spector TD Voumllzke H Watkins H Wilson JF Groop LC Haritunians T Hu FB Kaplan RC Metspalu A North KE Schlessinger D Wareham NJ Hunter DJ OConnell JR Strachan DP Wichmann HE Borecki IB van Duijn CM Schadt EE Thorsteinsdottir U Peltonen L Uitterlinden AG Visscher PM Chatterjee N Loos RJ Boehnke M McCarthy MI Ingelsson E Lindgren CM Abecasis GR Stefansson K Frayling TM Hirschhorn JN
Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen et alNature 2010 Oct 14467(7317)832-8
RISK SCORE METHOD
PROCAMFramingham Classical Risk factors
0
025
05
075
1
10 105 11 115 12 125 13 135
Risk Score
Pro
ba
bil
ity
no CHD CHD Set Specificity at
5 False Positive
in no-CAD
11 of men who get
CAD have baseline
score over cut-off
89 of the events that occurred over 10 years
would not be predicted by the score
Can we improve on this with genotypes
Whıch genes
to study
20
Genotype - smoking interactions
in risk score
Better than classical +
genotypes plt00001
Adding Environment-Genotype interactions
enhances (DOUBLES) risk prediction score
0
02
04
06
6 7 8 9 10 11 12
Risk score
pro
bab
ilit
y
no CHD CHD
EVEN BETTER
24 of cases
have score
over cut-off
5 FPR
Classical Risk factors + Genotypes + Smokıng
22
2001
Cui Y Wei QQ Park HK amp Lieber CM Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species Science 293 1289ndash1292 (2001)
ldquoDevices based on nanowires are emerging as a powerful platform for the direct detection of biological and chemical species including low concentrations of proteins and virusesrdquo 1st July 2006 Analytic Chemistry
No
rma
lise
d
con
du
ctan
ce c
han
ge
Figure 18 | taken from E Stern JF Klemic DA Routenberg PN Wyrembak DB
Turner-Evans AD Hamilton DA LaVan TM Fahmy and MA Reed Label-free
immunodetection with CMOS-compatible semiconducting nanowires Nature 445
05498 (2007)
Born April 2014
Nanowire chip
DNA extraction
PCR
ldquoHandheldrdquo
Arrived from the engineers at A Star Singapore LAST WEEK
First cassettes Chloroquine resistant Malaria warfarin BRAF
tumour marker
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated
Family at risk of breast cancer due to p53 mutation
Breast Cancer
bull 4 high penetrance genes
ndash BRCA1 breastovarian
ndash BRCA2 breastovarian
ndash P53 breast+sarcoma+others
ndash PTEN breast + thyroid+overgrowth
I1 I2
55
II2
49
II1 II3
45
For individual III1Calculated risk of cancer (20Heterozygote risk 190
10 year risk 0920 year risk 4430 year risk 97
Lifetime risk (85) 243
familial breast cancer
Individual III 1 at 20
Heterozygote 19
10 year risk 09
20 year risk 44
30 year risk 97
Lifetime risk 24
PARP inhibitors mechanism
DNA DSB
ATMR
ERCC1 XRCC3
NBS1 MRE11
Rad50 BRCA1
gH2AX
HR repair
DNA SSB
DNA replication
BER PARP
XRCC1
Pol Lig III
FA core complex FANC
D2
Rad 524 RPA
Rad 51 BRCA2
bull Endogenously formed SSB are normally repaired by PARP-dependent BER
bull If PARP is inhibited SSB persist
bull SSB form DSB at replication which are repaired by HR
bull If HR is defective the breaks are not repaired and the cell dies
bull This is the first exploitation of synthetic lethality in cancer therapy
Lynch syndrome
Endometrial
Carcinoma
Bertha
Ted
3 CRC
9 skin
cancers
Family from which DNA used to Demonstrate hMSH2 mutation by Kolodnerrsquos group 1993 1st of the MISMATCH REPAIR GENE DEFECTS
Muir Torre syndrome A sub type of Lynch syndrome
ndash Microsatellites are lengths of short repeated sequences usually
ndash mononucleotides eg BAT25
tgttttgtttttttgatttttttttttttttttttttttttgagaacagagca
ndash or dinucleotides eg D5S346
aatttacacacacacacacacacacacacacacagagta
Microsatellites
600mg aspirinday for 2 yrs reduced Lynch syndrome cancers at 5 yrs
by over 50
Lancet volume 378 December 11th 2011
CAPP2 follow up data May 2013
30
10
40
20
45434
25427
12 years New colorectal cancers in blinded recruits treated for mean 25 yrs with 600mg Aspirin (green) or placebo (red) Unpublished data
= Washington University
Genome Sequencing Center
Baylor College of Medicine
Human Genome Sequencing Center
Using AB 3730 XL
fluorescent Sanger chemistry
on capillary sequencers
per month
Sequencing 2005
Next-generation sequencers
Slide courtesy of
John D McPherson OICR
Sequencing Now
First woman sequenced June 2008
Human amp Clinical Genetics
Marjolein Kriek PhD clinical geneticist
34
ldquoMan takes one step towards understanding womanrdquo
Human Genomics Strategy Group bull Government response
ndash 100000 whole genomes ndash pound100 million investment ndash Genomics Strategy Board
(NHS now HEE)
Newcastle one of four pilot centres 209743 rare disease samples (130114)
3 million
Error rates inadequate depth of coverage
copy number variation imprinted genes
splice variants
W hole genome sequencing
Functional classification of JDW SNPs
SNP Type Known SNPs Novel SNPs
Missense 8967 2421
Nonsense 44 5
Synonymous 9121 2261
UTR 18517 7102
Intron 922048 381924
August 2010 China National Highway 110 traffic jam China worldrsquos worst
traffic jam everhellip
more than 100 kilometres from August 14 - 26 inc at least 11 days of total
gridlock
We are heading for the biggest traffic jam in history
Hereditary colorectal cancer Should I request colonoscopy
Donna-Marie Ian
25 24
Positive FH
MSI high tumour
MLH1 leu559arg
Missense
Not inherited
Robert Hofstra
Rolf Sijmons
Westernno expression
Pulldown no interaction
MAPP-MMR and SIFT v2
Suggest pathogenic
Polyphen inconclusive
Reported Belvederesi EJHG
2006
Grantham Variation (GV) and Deviation (GD)
C
P
V Grantham R Science 185 862-864 1974
Tavtigian et al JMG 43 295 2006
GV
GD
HVP4 UNESCO Headquarters Paris 11-15 June 2012
Estimates of Heritability
Disorder Frequency () ()
bull Schizophrenia 1 85
bull Asthma 4 80
bull Ankylosing spondylitis 02 70
bull Neural tube defects 02 60
bull Congenital heart disease 05 60
21
bull Paper by Galton
ldquoChildren regress to
Mediocrityrdquo
Imagine if there were only 2 genes for height each with only 2 alleles H or T of equal
frequency
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
10
We discover one of the genes and call it BYH1 somebody would suggest using it for disease
prediction
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
average short Very
short tall
Very
tall
Always bump
your head
Often bump
Your head
ldquohundreds of variants in at least 180 loci influence human heightrdquo
Nature 2010 Oct 14467(7317)832-8 doi 101038nature09410 Epub 2010 Sep 29 Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen H1 Estrada K Lettre G Berndt SI Weedon MN Rivadeneira F Willer CJ Jackson AU Vedantam S Raychaudhuri S Ferreira T Wood AR Weyant RJ Segregrave AV Speliotes EK Wheeler E Soranzo N Park JH Yang J Gudbjartsson D Heard-Costa NL Randall JC Qi L Vernon Smith A Maumlgi R Pastinen T Liang L Heid IM Luan J Thorleifsson G Winkler TW Goddard ME Sin Lo K Palmer C Workalemahu T Aulchenko YS Johansson A Zillikens MC Feitosa MF Esko T Johnson T Ketkar S Kraft P Mangino M Prokopenko I Absher D Albrecht E Ernst F Glazer NL Hayward C Hottenga JJ Jacobs KB Knowles JW Kutalik Z Monda KL Polasek O Preuss M Rayner NW Robertson NR Steinthorsdottir V Tyrer JP Voight BF Wiklund F Xu J Zhao JH Nyholt DR Pellikka N Perola M Perry JR Surakka I Tammesoo ML Altmaier EL Amin N Aspelund T Bhangale T Boucher G Chasman DI Chen C Coin L Cooper MN Dixon AL Gibson Q Grundberg E Hao K Juhani Junttila M Kaplan LM Kettunen J Koumlnig IR Kwan T Lawrence RW Levinson DF Lorentzon M McKnight B Morris AP Muumlller M Suh Ngwa J Purcell S Rafelt S Salem RM Salvi E Sanna S Shi J Sovio U Thompson JR Turchin MC Vandenput L Verlaan DJ Vitart V White CC Ziegler A Almgren P Balmforth AJ Campbell H Citterio L De Grandi A Dominiczak A Duan J Elliott P Elosua R Eriksson JG Freimer NB Geus EJ Glorioso N Haiqing S Hartikainen AL Havulinna AS Hicks AA Hui J Igl W Illig T Jula A Kajantie E Kilpelaumlinen TO Koiranen M Kolcic I Koskinen S Kovacs P Laitinen J Liu J Lokki ML Marusic A Maschio A Meitinger T Mulas A Pareacute G Parker AN Peden JF Petersmann A Pichler I Pietilaumlinen KH Pouta A Ridderstraringle M Rotter JI Sambrook JG Sanders AR Schmidt CO Sinisalo J Smit JH Stringham HM Bragi Walters G Widen E Wild SH Willemsen G Zagato L Zgaga L Zitting P Alavere H Farrall M McArdle WL Nelis M Peters MJ Ripatti S van Meurs JB Aben KK Ardlie KG Beckmann JS Beilby JP Bergman RN Bergmann S Collins FS Cusi D den Heijer M Eiriksdottir G Gejman PV Hall AS Hamsten A Huikuri HV Iribarren C Kaumlhoumlnen M Kaprio J Kathiresan S Kiemeney L Kocher T Launer LJ Lehtimaumlki T Melander O Mosley TH Jr Musk AW Nieminen MS ODonnell CJ Ohlsson C Oostra B Palmer LJ Raitakari O Ridker PM Rioux JD Rissanen A Rivolta C Schunkert H Shuldiner AR Siscovick DS Stumvoll M Toumlnjes A Tuomilehto J van Ommen GJ Viikari J Heath AC Martin NG Montgomery GW Province MA Kayser M Arnold AM Atwood LD Boerwinkle E Chanock SJ Deloukas P Gieger C Groumlnberg H Hall P Hattersley AT Hengstenberg C Hoffman W Lathrop GM Salomaa V Schreiber S Uda M Waterworth D Wright AF Assimes TL Barroso I Hofman A Mohlke KL Boomsma DI Caulfield MJ Cupples LA Erdmann J Fox CS Gudnason V Gyllensten U Harris TB Hayes RB Jarvelin MR Mooser V Munroe PB Ouwehand WH Penninx BW Pramstaller PP Quertermous T Rudan I Samani NJ Spector TD Voumllzke H Watkins H Wilson JF Groop LC Haritunians T Hu FB Kaplan RC Metspalu A North KE Schlessinger D Wareham NJ Hunter DJ OConnell JR Strachan DP Wichmann HE Borecki IB van Duijn CM Schadt EE Thorsteinsdottir U Peltonen L Uitterlinden AG Visscher PM Chatterjee N Loos RJ Boehnke M McCarthy MI Ingelsson E Lindgren CM Abecasis GR Stefansson K Frayling TM Hirschhorn JN
Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen et alNature 2010 Oct 14467(7317)832-8
RISK SCORE METHOD
PROCAMFramingham Classical Risk factors
0
025
05
075
1
10 105 11 115 12 125 13 135
Risk Score
Pro
ba
bil
ity
no CHD CHD Set Specificity at
5 False Positive
in no-CAD
11 of men who get
CAD have baseline
score over cut-off
89 of the events that occurred over 10 years
would not be predicted by the score
Can we improve on this with genotypes
Whıch genes
to study
20
Genotype - smoking interactions
in risk score
Better than classical +
genotypes plt00001
Adding Environment-Genotype interactions
enhances (DOUBLES) risk prediction score
0
02
04
06
6 7 8 9 10 11 12
Risk score
pro
bab
ilit
y
no CHD CHD
EVEN BETTER
24 of cases
have score
over cut-off
5 FPR
Classical Risk factors + Genotypes + Smokıng
22
2001
Cui Y Wei QQ Park HK amp Lieber CM Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species Science 293 1289ndash1292 (2001)
ldquoDevices based on nanowires are emerging as a powerful platform for the direct detection of biological and chemical species including low concentrations of proteins and virusesrdquo 1st July 2006 Analytic Chemistry
No
rma
lise
d
con
du
ctan
ce c
han
ge
Figure 18 | taken from E Stern JF Klemic DA Routenberg PN Wyrembak DB
Turner-Evans AD Hamilton DA LaVan TM Fahmy and MA Reed Label-free
immunodetection with CMOS-compatible semiconducting nanowires Nature 445
05498 (2007)
Born April 2014
Nanowire chip
DNA extraction
PCR
ldquoHandheldrdquo
Arrived from the engineers at A Star Singapore LAST WEEK
First cassettes Chloroquine resistant Malaria warfarin BRAF
tumour marker
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated
Breast Cancer
bull 4 high penetrance genes
ndash BRCA1 breastovarian
ndash BRCA2 breastovarian
ndash P53 breast+sarcoma+others
ndash PTEN breast + thyroid+overgrowth
I1 I2
55
II2
49
II1 II3
45
For individual III1Calculated risk of cancer (20Heterozygote risk 190
10 year risk 0920 year risk 4430 year risk 97
Lifetime risk (85) 243
familial breast cancer
Individual III 1 at 20
Heterozygote 19
10 year risk 09
20 year risk 44
30 year risk 97
Lifetime risk 24
PARP inhibitors mechanism
DNA DSB
ATMR
ERCC1 XRCC3
NBS1 MRE11
Rad50 BRCA1
gH2AX
HR repair
DNA SSB
DNA replication
BER PARP
XRCC1
Pol Lig III
FA core complex FANC
D2
Rad 524 RPA
Rad 51 BRCA2
bull Endogenously formed SSB are normally repaired by PARP-dependent BER
bull If PARP is inhibited SSB persist
bull SSB form DSB at replication which are repaired by HR
bull If HR is defective the breaks are not repaired and the cell dies
bull This is the first exploitation of synthetic lethality in cancer therapy
Lynch syndrome
Endometrial
Carcinoma
Bertha
Ted
3 CRC
9 skin
cancers
Family from which DNA used to Demonstrate hMSH2 mutation by Kolodnerrsquos group 1993 1st of the MISMATCH REPAIR GENE DEFECTS
Muir Torre syndrome A sub type of Lynch syndrome
ndash Microsatellites are lengths of short repeated sequences usually
ndash mononucleotides eg BAT25
tgttttgtttttttgatttttttttttttttttttttttttgagaacagagca
ndash or dinucleotides eg D5S346
aatttacacacacacacacacacacacacacacagagta
Microsatellites
600mg aspirinday for 2 yrs reduced Lynch syndrome cancers at 5 yrs
by over 50
Lancet volume 378 December 11th 2011
CAPP2 follow up data May 2013
30
10
40
20
45434
25427
12 years New colorectal cancers in blinded recruits treated for mean 25 yrs with 600mg Aspirin (green) or placebo (red) Unpublished data
= Washington University
Genome Sequencing Center
Baylor College of Medicine
Human Genome Sequencing Center
Using AB 3730 XL
fluorescent Sanger chemistry
on capillary sequencers
per month
Sequencing 2005
Next-generation sequencers
Slide courtesy of
John D McPherson OICR
Sequencing Now
First woman sequenced June 2008
Human amp Clinical Genetics
Marjolein Kriek PhD clinical geneticist
34
ldquoMan takes one step towards understanding womanrdquo
Human Genomics Strategy Group bull Government response
ndash 100000 whole genomes ndash pound100 million investment ndash Genomics Strategy Board
(NHS now HEE)
Newcastle one of four pilot centres 209743 rare disease samples (130114)
3 million
Error rates inadequate depth of coverage
copy number variation imprinted genes
splice variants
W hole genome sequencing
Functional classification of JDW SNPs
SNP Type Known SNPs Novel SNPs
Missense 8967 2421
Nonsense 44 5
Synonymous 9121 2261
UTR 18517 7102
Intron 922048 381924
August 2010 China National Highway 110 traffic jam China worldrsquos worst
traffic jam everhellip
more than 100 kilometres from August 14 - 26 inc at least 11 days of total
gridlock
We are heading for the biggest traffic jam in history
Hereditary colorectal cancer Should I request colonoscopy
Donna-Marie Ian
25 24
Positive FH
MSI high tumour
MLH1 leu559arg
Missense
Not inherited
Robert Hofstra
Rolf Sijmons
Westernno expression
Pulldown no interaction
MAPP-MMR and SIFT v2
Suggest pathogenic
Polyphen inconclusive
Reported Belvederesi EJHG
2006
Grantham Variation (GV) and Deviation (GD)
C
P
V Grantham R Science 185 862-864 1974
Tavtigian et al JMG 43 295 2006
GV
GD
HVP4 UNESCO Headquarters Paris 11-15 June 2012
Estimates of Heritability
Disorder Frequency () ()
bull Schizophrenia 1 85
bull Asthma 4 80
bull Ankylosing spondylitis 02 70
bull Neural tube defects 02 60
bull Congenital heart disease 05 60
21
bull Paper by Galton
ldquoChildren regress to
Mediocrityrdquo
Imagine if there were only 2 genes for height each with only 2 alleles H or T of equal
frequency
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
10
We discover one of the genes and call it BYH1 somebody would suggest using it for disease
prediction
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
average short Very
short tall
Very
tall
Always bump
your head
Often bump
Your head
ldquohundreds of variants in at least 180 loci influence human heightrdquo
Nature 2010 Oct 14467(7317)832-8 doi 101038nature09410 Epub 2010 Sep 29 Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen H1 Estrada K Lettre G Berndt SI Weedon MN Rivadeneira F Willer CJ Jackson AU Vedantam S Raychaudhuri S Ferreira T Wood AR Weyant RJ Segregrave AV Speliotes EK Wheeler E Soranzo N Park JH Yang J Gudbjartsson D Heard-Costa NL Randall JC Qi L Vernon Smith A Maumlgi R Pastinen T Liang L Heid IM Luan J Thorleifsson G Winkler TW Goddard ME Sin Lo K Palmer C Workalemahu T Aulchenko YS Johansson A Zillikens MC Feitosa MF Esko T Johnson T Ketkar S Kraft P Mangino M Prokopenko I Absher D Albrecht E Ernst F Glazer NL Hayward C Hottenga JJ Jacobs KB Knowles JW Kutalik Z Monda KL Polasek O Preuss M Rayner NW Robertson NR Steinthorsdottir V Tyrer JP Voight BF Wiklund F Xu J Zhao JH Nyholt DR Pellikka N Perola M Perry JR Surakka I Tammesoo ML Altmaier EL Amin N Aspelund T Bhangale T Boucher G Chasman DI Chen C Coin L Cooper MN Dixon AL Gibson Q Grundberg E Hao K Juhani Junttila M Kaplan LM Kettunen J Koumlnig IR Kwan T Lawrence RW Levinson DF Lorentzon M McKnight B Morris AP Muumlller M Suh Ngwa J Purcell S Rafelt S Salem RM Salvi E Sanna S Shi J Sovio U Thompson JR Turchin MC Vandenput L Verlaan DJ Vitart V White CC Ziegler A Almgren P Balmforth AJ Campbell H Citterio L De Grandi A Dominiczak A Duan J Elliott P Elosua R Eriksson JG Freimer NB Geus EJ Glorioso N Haiqing S Hartikainen AL Havulinna AS Hicks AA Hui J Igl W Illig T Jula A Kajantie E Kilpelaumlinen TO Koiranen M Kolcic I Koskinen S Kovacs P Laitinen J Liu J Lokki ML Marusic A Maschio A Meitinger T Mulas A Pareacute G Parker AN Peden JF Petersmann A Pichler I Pietilaumlinen KH Pouta A Ridderstraringle M Rotter JI Sambrook JG Sanders AR Schmidt CO Sinisalo J Smit JH Stringham HM Bragi Walters G Widen E Wild SH Willemsen G Zagato L Zgaga L Zitting P Alavere H Farrall M McArdle WL Nelis M Peters MJ Ripatti S van Meurs JB Aben KK Ardlie KG Beckmann JS Beilby JP Bergman RN Bergmann S Collins FS Cusi D den Heijer M Eiriksdottir G Gejman PV Hall AS Hamsten A Huikuri HV Iribarren C Kaumlhoumlnen M Kaprio J Kathiresan S Kiemeney L Kocher T Launer LJ Lehtimaumlki T Melander O Mosley TH Jr Musk AW Nieminen MS ODonnell CJ Ohlsson C Oostra B Palmer LJ Raitakari O Ridker PM Rioux JD Rissanen A Rivolta C Schunkert H Shuldiner AR Siscovick DS Stumvoll M Toumlnjes A Tuomilehto J van Ommen GJ Viikari J Heath AC Martin NG Montgomery GW Province MA Kayser M Arnold AM Atwood LD Boerwinkle E Chanock SJ Deloukas P Gieger C Groumlnberg H Hall P Hattersley AT Hengstenberg C Hoffman W Lathrop GM Salomaa V Schreiber S Uda M Waterworth D Wright AF Assimes TL Barroso I Hofman A Mohlke KL Boomsma DI Caulfield MJ Cupples LA Erdmann J Fox CS Gudnason V Gyllensten U Harris TB Hayes RB Jarvelin MR Mooser V Munroe PB Ouwehand WH Penninx BW Pramstaller PP Quertermous T Rudan I Samani NJ Spector TD Voumllzke H Watkins H Wilson JF Groop LC Haritunians T Hu FB Kaplan RC Metspalu A North KE Schlessinger D Wareham NJ Hunter DJ OConnell JR Strachan DP Wichmann HE Borecki IB van Duijn CM Schadt EE Thorsteinsdottir U Peltonen L Uitterlinden AG Visscher PM Chatterjee N Loos RJ Boehnke M McCarthy MI Ingelsson E Lindgren CM Abecasis GR Stefansson K Frayling TM Hirschhorn JN
Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen et alNature 2010 Oct 14467(7317)832-8
RISK SCORE METHOD
PROCAMFramingham Classical Risk factors
0
025
05
075
1
10 105 11 115 12 125 13 135
Risk Score
Pro
ba
bil
ity
no CHD CHD Set Specificity at
5 False Positive
in no-CAD
11 of men who get
CAD have baseline
score over cut-off
89 of the events that occurred over 10 years
would not be predicted by the score
Can we improve on this with genotypes
Whıch genes
to study
20
Genotype - smoking interactions
in risk score
Better than classical +
genotypes plt00001
Adding Environment-Genotype interactions
enhances (DOUBLES) risk prediction score
0
02
04
06
6 7 8 9 10 11 12
Risk score
pro
bab
ilit
y
no CHD CHD
EVEN BETTER
24 of cases
have score
over cut-off
5 FPR
Classical Risk factors + Genotypes + Smokıng
22
2001
Cui Y Wei QQ Park HK amp Lieber CM Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species Science 293 1289ndash1292 (2001)
ldquoDevices based on nanowires are emerging as a powerful platform for the direct detection of biological and chemical species including low concentrations of proteins and virusesrdquo 1st July 2006 Analytic Chemistry
No
rma
lise
d
con
du
ctan
ce c
han
ge
Figure 18 | taken from E Stern JF Klemic DA Routenberg PN Wyrembak DB
Turner-Evans AD Hamilton DA LaVan TM Fahmy and MA Reed Label-free
immunodetection with CMOS-compatible semiconducting nanowires Nature 445
05498 (2007)
Born April 2014
Nanowire chip
DNA extraction
PCR
ldquoHandheldrdquo
Arrived from the engineers at A Star Singapore LAST WEEK
First cassettes Chloroquine resistant Malaria warfarin BRAF
tumour marker
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated
I1 I2
55
II2
49
II1 II3
45
For individual III1Calculated risk of cancer (20Heterozygote risk 190
10 year risk 0920 year risk 4430 year risk 97
Lifetime risk (85) 243
familial breast cancer
Individual III 1 at 20
Heterozygote 19
10 year risk 09
20 year risk 44
30 year risk 97
Lifetime risk 24
PARP inhibitors mechanism
DNA DSB
ATMR
ERCC1 XRCC3
NBS1 MRE11
Rad50 BRCA1
gH2AX
HR repair
DNA SSB
DNA replication
BER PARP
XRCC1
Pol Lig III
FA core complex FANC
D2
Rad 524 RPA
Rad 51 BRCA2
bull Endogenously formed SSB are normally repaired by PARP-dependent BER
bull If PARP is inhibited SSB persist
bull SSB form DSB at replication which are repaired by HR
bull If HR is defective the breaks are not repaired and the cell dies
bull This is the first exploitation of synthetic lethality in cancer therapy
Lynch syndrome
Endometrial
Carcinoma
Bertha
Ted
3 CRC
9 skin
cancers
Family from which DNA used to Demonstrate hMSH2 mutation by Kolodnerrsquos group 1993 1st of the MISMATCH REPAIR GENE DEFECTS
Muir Torre syndrome A sub type of Lynch syndrome
ndash Microsatellites are lengths of short repeated sequences usually
ndash mononucleotides eg BAT25
tgttttgtttttttgatttttttttttttttttttttttttgagaacagagca
ndash or dinucleotides eg D5S346
aatttacacacacacacacacacacacacacacagagta
Microsatellites
600mg aspirinday for 2 yrs reduced Lynch syndrome cancers at 5 yrs
by over 50
Lancet volume 378 December 11th 2011
CAPP2 follow up data May 2013
30
10
40
20
45434
25427
12 years New colorectal cancers in blinded recruits treated for mean 25 yrs with 600mg Aspirin (green) or placebo (red) Unpublished data
= Washington University
Genome Sequencing Center
Baylor College of Medicine
Human Genome Sequencing Center
Using AB 3730 XL
fluorescent Sanger chemistry
on capillary sequencers
per month
Sequencing 2005
Next-generation sequencers
Slide courtesy of
John D McPherson OICR
Sequencing Now
First woman sequenced June 2008
Human amp Clinical Genetics
Marjolein Kriek PhD clinical geneticist
34
ldquoMan takes one step towards understanding womanrdquo
Human Genomics Strategy Group bull Government response
ndash 100000 whole genomes ndash pound100 million investment ndash Genomics Strategy Board
(NHS now HEE)
Newcastle one of four pilot centres 209743 rare disease samples (130114)
3 million
Error rates inadequate depth of coverage
copy number variation imprinted genes
splice variants
W hole genome sequencing
Functional classification of JDW SNPs
SNP Type Known SNPs Novel SNPs
Missense 8967 2421
Nonsense 44 5
Synonymous 9121 2261
UTR 18517 7102
Intron 922048 381924
August 2010 China National Highway 110 traffic jam China worldrsquos worst
traffic jam everhellip
more than 100 kilometres from August 14 - 26 inc at least 11 days of total
gridlock
We are heading for the biggest traffic jam in history
Hereditary colorectal cancer Should I request colonoscopy
Donna-Marie Ian
25 24
Positive FH
MSI high tumour
MLH1 leu559arg
Missense
Not inherited
Robert Hofstra
Rolf Sijmons
Westernno expression
Pulldown no interaction
MAPP-MMR and SIFT v2
Suggest pathogenic
Polyphen inconclusive
Reported Belvederesi EJHG
2006
Grantham Variation (GV) and Deviation (GD)
C
P
V Grantham R Science 185 862-864 1974
Tavtigian et al JMG 43 295 2006
GV
GD
HVP4 UNESCO Headquarters Paris 11-15 June 2012
Estimates of Heritability
Disorder Frequency () ()
bull Schizophrenia 1 85
bull Asthma 4 80
bull Ankylosing spondylitis 02 70
bull Neural tube defects 02 60
bull Congenital heart disease 05 60
21
bull Paper by Galton
ldquoChildren regress to
Mediocrityrdquo
Imagine if there were only 2 genes for height each with only 2 alleles H or T of equal
frequency
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
10
We discover one of the genes and call it BYH1 somebody would suggest using it for disease
prediction
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
average short Very
short tall
Very
tall
Always bump
your head
Often bump
Your head
ldquohundreds of variants in at least 180 loci influence human heightrdquo
Nature 2010 Oct 14467(7317)832-8 doi 101038nature09410 Epub 2010 Sep 29 Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen H1 Estrada K Lettre G Berndt SI Weedon MN Rivadeneira F Willer CJ Jackson AU Vedantam S Raychaudhuri S Ferreira T Wood AR Weyant RJ Segregrave AV Speliotes EK Wheeler E Soranzo N Park JH Yang J Gudbjartsson D Heard-Costa NL Randall JC Qi L Vernon Smith A Maumlgi R Pastinen T Liang L Heid IM Luan J Thorleifsson G Winkler TW Goddard ME Sin Lo K Palmer C Workalemahu T Aulchenko YS Johansson A Zillikens MC Feitosa MF Esko T Johnson T Ketkar S Kraft P Mangino M Prokopenko I Absher D Albrecht E Ernst F Glazer NL Hayward C Hottenga JJ Jacobs KB Knowles JW Kutalik Z Monda KL Polasek O Preuss M Rayner NW Robertson NR Steinthorsdottir V Tyrer JP Voight BF Wiklund F Xu J Zhao JH Nyholt DR Pellikka N Perola M Perry JR Surakka I Tammesoo ML Altmaier EL Amin N Aspelund T Bhangale T Boucher G Chasman DI Chen C Coin L Cooper MN Dixon AL Gibson Q Grundberg E Hao K Juhani Junttila M Kaplan LM Kettunen J Koumlnig IR Kwan T Lawrence RW Levinson DF Lorentzon M McKnight B Morris AP Muumlller M Suh Ngwa J Purcell S Rafelt S Salem RM Salvi E Sanna S Shi J Sovio U Thompson JR Turchin MC Vandenput L Verlaan DJ Vitart V White CC Ziegler A Almgren P Balmforth AJ Campbell H Citterio L De Grandi A Dominiczak A Duan J Elliott P Elosua R Eriksson JG Freimer NB Geus EJ Glorioso N Haiqing S Hartikainen AL Havulinna AS Hicks AA Hui J Igl W Illig T Jula A Kajantie E Kilpelaumlinen TO Koiranen M Kolcic I Koskinen S Kovacs P Laitinen J Liu J Lokki ML Marusic A Maschio A Meitinger T Mulas A Pareacute G Parker AN Peden JF Petersmann A Pichler I Pietilaumlinen KH Pouta A Ridderstraringle M Rotter JI Sambrook JG Sanders AR Schmidt CO Sinisalo J Smit JH Stringham HM Bragi Walters G Widen E Wild SH Willemsen G Zagato L Zgaga L Zitting P Alavere H Farrall M McArdle WL Nelis M Peters MJ Ripatti S van Meurs JB Aben KK Ardlie KG Beckmann JS Beilby JP Bergman RN Bergmann S Collins FS Cusi D den Heijer M Eiriksdottir G Gejman PV Hall AS Hamsten A Huikuri HV Iribarren C Kaumlhoumlnen M Kaprio J Kathiresan S Kiemeney L Kocher T Launer LJ Lehtimaumlki T Melander O Mosley TH Jr Musk AW Nieminen MS ODonnell CJ Ohlsson C Oostra B Palmer LJ Raitakari O Ridker PM Rioux JD Rissanen A Rivolta C Schunkert H Shuldiner AR Siscovick DS Stumvoll M Toumlnjes A Tuomilehto J van Ommen GJ Viikari J Heath AC Martin NG Montgomery GW Province MA Kayser M Arnold AM Atwood LD Boerwinkle E Chanock SJ Deloukas P Gieger C Groumlnberg H Hall P Hattersley AT Hengstenberg C Hoffman W Lathrop GM Salomaa V Schreiber S Uda M Waterworth D Wright AF Assimes TL Barroso I Hofman A Mohlke KL Boomsma DI Caulfield MJ Cupples LA Erdmann J Fox CS Gudnason V Gyllensten U Harris TB Hayes RB Jarvelin MR Mooser V Munroe PB Ouwehand WH Penninx BW Pramstaller PP Quertermous T Rudan I Samani NJ Spector TD Voumllzke H Watkins H Wilson JF Groop LC Haritunians T Hu FB Kaplan RC Metspalu A North KE Schlessinger D Wareham NJ Hunter DJ OConnell JR Strachan DP Wichmann HE Borecki IB van Duijn CM Schadt EE Thorsteinsdottir U Peltonen L Uitterlinden AG Visscher PM Chatterjee N Loos RJ Boehnke M McCarthy MI Ingelsson E Lindgren CM Abecasis GR Stefansson K Frayling TM Hirschhorn JN
Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen et alNature 2010 Oct 14467(7317)832-8
RISK SCORE METHOD
PROCAMFramingham Classical Risk factors
0
025
05
075
1
10 105 11 115 12 125 13 135
Risk Score
Pro
ba
bil
ity
no CHD CHD Set Specificity at
5 False Positive
in no-CAD
11 of men who get
CAD have baseline
score over cut-off
89 of the events that occurred over 10 years
would not be predicted by the score
Can we improve on this with genotypes
Whıch genes
to study
20
Genotype - smoking interactions
in risk score
Better than classical +
genotypes plt00001
Adding Environment-Genotype interactions
enhances (DOUBLES) risk prediction score
0
02
04
06
6 7 8 9 10 11 12
Risk score
pro
bab
ilit
y
no CHD CHD
EVEN BETTER
24 of cases
have score
over cut-off
5 FPR
Classical Risk factors + Genotypes + Smokıng
22
2001
Cui Y Wei QQ Park HK amp Lieber CM Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species Science 293 1289ndash1292 (2001)
ldquoDevices based on nanowires are emerging as a powerful platform for the direct detection of biological and chemical species including low concentrations of proteins and virusesrdquo 1st July 2006 Analytic Chemistry
No
rma
lise
d
con
du
ctan
ce c
han
ge
Figure 18 | taken from E Stern JF Klemic DA Routenberg PN Wyrembak DB
Turner-Evans AD Hamilton DA LaVan TM Fahmy and MA Reed Label-free
immunodetection with CMOS-compatible semiconducting nanowires Nature 445
05498 (2007)
Born April 2014
Nanowire chip
DNA extraction
PCR
ldquoHandheldrdquo
Arrived from the engineers at A Star Singapore LAST WEEK
First cassettes Chloroquine resistant Malaria warfarin BRAF
tumour marker
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated
PARP inhibitors mechanism
DNA DSB
ATMR
ERCC1 XRCC3
NBS1 MRE11
Rad50 BRCA1
gH2AX
HR repair
DNA SSB
DNA replication
BER PARP
XRCC1
Pol Lig III
FA core complex FANC
D2
Rad 524 RPA
Rad 51 BRCA2
bull Endogenously formed SSB are normally repaired by PARP-dependent BER
bull If PARP is inhibited SSB persist
bull SSB form DSB at replication which are repaired by HR
bull If HR is defective the breaks are not repaired and the cell dies
bull This is the first exploitation of synthetic lethality in cancer therapy
Lynch syndrome
Endometrial
Carcinoma
Bertha
Ted
3 CRC
9 skin
cancers
Family from which DNA used to Demonstrate hMSH2 mutation by Kolodnerrsquos group 1993 1st of the MISMATCH REPAIR GENE DEFECTS
Muir Torre syndrome A sub type of Lynch syndrome
ndash Microsatellites are lengths of short repeated sequences usually
ndash mononucleotides eg BAT25
tgttttgtttttttgatttttttttttttttttttttttttgagaacagagca
ndash or dinucleotides eg D5S346
aatttacacacacacacacacacacacacacacagagta
Microsatellites
600mg aspirinday for 2 yrs reduced Lynch syndrome cancers at 5 yrs
by over 50
Lancet volume 378 December 11th 2011
CAPP2 follow up data May 2013
30
10
40
20
45434
25427
12 years New colorectal cancers in blinded recruits treated for mean 25 yrs with 600mg Aspirin (green) or placebo (red) Unpublished data
= Washington University
Genome Sequencing Center
Baylor College of Medicine
Human Genome Sequencing Center
Using AB 3730 XL
fluorescent Sanger chemistry
on capillary sequencers
per month
Sequencing 2005
Next-generation sequencers
Slide courtesy of
John D McPherson OICR
Sequencing Now
First woman sequenced June 2008
Human amp Clinical Genetics
Marjolein Kriek PhD clinical geneticist
34
ldquoMan takes one step towards understanding womanrdquo
Human Genomics Strategy Group bull Government response
ndash 100000 whole genomes ndash pound100 million investment ndash Genomics Strategy Board
(NHS now HEE)
Newcastle one of four pilot centres 209743 rare disease samples (130114)
3 million
Error rates inadequate depth of coverage
copy number variation imprinted genes
splice variants
W hole genome sequencing
Functional classification of JDW SNPs
SNP Type Known SNPs Novel SNPs
Missense 8967 2421
Nonsense 44 5
Synonymous 9121 2261
UTR 18517 7102
Intron 922048 381924
August 2010 China National Highway 110 traffic jam China worldrsquos worst
traffic jam everhellip
more than 100 kilometres from August 14 - 26 inc at least 11 days of total
gridlock
We are heading for the biggest traffic jam in history
Hereditary colorectal cancer Should I request colonoscopy
Donna-Marie Ian
25 24
Positive FH
MSI high tumour
MLH1 leu559arg
Missense
Not inherited
Robert Hofstra
Rolf Sijmons
Westernno expression
Pulldown no interaction
MAPP-MMR and SIFT v2
Suggest pathogenic
Polyphen inconclusive
Reported Belvederesi EJHG
2006
Grantham Variation (GV) and Deviation (GD)
C
P
V Grantham R Science 185 862-864 1974
Tavtigian et al JMG 43 295 2006
GV
GD
HVP4 UNESCO Headquarters Paris 11-15 June 2012
Estimates of Heritability
Disorder Frequency () ()
bull Schizophrenia 1 85
bull Asthma 4 80
bull Ankylosing spondylitis 02 70
bull Neural tube defects 02 60
bull Congenital heart disease 05 60
21
bull Paper by Galton
ldquoChildren regress to
Mediocrityrdquo
Imagine if there were only 2 genes for height each with only 2 alleles H or T of equal
frequency
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
10
We discover one of the genes and call it BYH1 somebody would suggest using it for disease
prediction
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
average short Very
short tall
Very
tall
Always bump
your head
Often bump
Your head
ldquohundreds of variants in at least 180 loci influence human heightrdquo
Nature 2010 Oct 14467(7317)832-8 doi 101038nature09410 Epub 2010 Sep 29 Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen H1 Estrada K Lettre G Berndt SI Weedon MN Rivadeneira F Willer CJ Jackson AU Vedantam S Raychaudhuri S Ferreira T Wood AR Weyant RJ Segregrave AV Speliotes EK Wheeler E Soranzo N Park JH Yang J Gudbjartsson D Heard-Costa NL Randall JC Qi L Vernon Smith A Maumlgi R Pastinen T Liang L Heid IM Luan J Thorleifsson G Winkler TW Goddard ME Sin Lo K Palmer C Workalemahu T Aulchenko YS Johansson A Zillikens MC Feitosa MF Esko T Johnson T Ketkar S Kraft P Mangino M Prokopenko I Absher D Albrecht E Ernst F Glazer NL Hayward C Hottenga JJ Jacobs KB Knowles JW Kutalik Z Monda KL Polasek O Preuss M Rayner NW Robertson NR Steinthorsdottir V Tyrer JP Voight BF Wiklund F Xu J Zhao JH Nyholt DR Pellikka N Perola M Perry JR Surakka I Tammesoo ML Altmaier EL Amin N Aspelund T Bhangale T Boucher G Chasman DI Chen C Coin L Cooper MN Dixon AL Gibson Q Grundberg E Hao K Juhani Junttila M Kaplan LM Kettunen J Koumlnig IR Kwan T Lawrence RW Levinson DF Lorentzon M McKnight B Morris AP Muumlller M Suh Ngwa J Purcell S Rafelt S Salem RM Salvi E Sanna S Shi J Sovio U Thompson JR Turchin MC Vandenput L Verlaan DJ Vitart V White CC Ziegler A Almgren P Balmforth AJ Campbell H Citterio L De Grandi A Dominiczak A Duan J Elliott P Elosua R Eriksson JG Freimer NB Geus EJ Glorioso N Haiqing S Hartikainen AL Havulinna AS Hicks AA Hui J Igl W Illig T Jula A Kajantie E Kilpelaumlinen TO Koiranen M Kolcic I Koskinen S Kovacs P Laitinen J Liu J Lokki ML Marusic A Maschio A Meitinger T Mulas A Pareacute G Parker AN Peden JF Petersmann A Pichler I Pietilaumlinen KH Pouta A Ridderstraringle M Rotter JI Sambrook JG Sanders AR Schmidt CO Sinisalo J Smit JH Stringham HM Bragi Walters G Widen E Wild SH Willemsen G Zagato L Zgaga L Zitting P Alavere H Farrall M McArdle WL Nelis M Peters MJ Ripatti S van Meurs JB Aben KK Ardlie KG Beckmann JS Beilby JP Bergman RN Bergmann S Collins FS Cusi D den Heijer M Eiriksdottir G Gejman PV Hall AS Hamsten A Huikuri HV Iribarren C Kaumlhoumlnen M Kaprio J Kathiresan S Kiemeney L Kocher T Launer LJ Lehtimaumlki T Melander O Mosley TH Jr Musk AW Nieminen MS ODonnell CJ Ohlsson C Oostra B Palmer LJ Raitakari O Ridker PM Rioux JD Rissanen A Rivolta C Schunkert H Shuldiner AR Siscovick DS Stumvoll M Toumlnjes A Tuomilehto J van Ommen GJ Viikari J Heath AC Martin NG Montgomery GW Province MA Kayser M Arnold AM Atwood LD Boerwinkle E Chanock SJ Deloukas P Gieger C Groumlnberg H Hall P Hattersley AT Hengstenberg C Hoffman W Lathrop GM Salomaa V Schreiber S Uda M Waterworth D Wright AF Assimes TL Barroso I Hofman A Mohlke KL Boomsma DI Caulfield MJ Cupples LA Erdmann J Fox CS Gudnason V Gyllensten U Harris TB Hayes RB Jarvelin MR Mooser V Munroe PB Ouwehand WH Penninx BW Pramstaller PP Quertermous T Rudan I Samani NJ Spector TD Voumllzke H Watkins H Wilson JF Groop LC Haritunians T Hu FB Kaplan RC Metspalu A North KE Schlessinger D Wareham NJ Hunter DJ OConnell JR Strachan DP Wichmann HE Borecki IB van Duijn CM Schadt EE Thorsteinsdottir U Peltonen L Uitterlinden AG Visscher PM Chatterjee N Loos RJ Boehnke M McCarthy MI Ingelsson E Lindgren CM Abecasis GR Stefansson K Frayling TM Hirschhorn JN
Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen et alNature 2010 Oct 14467(7317)832-8
RISK SCORE METHOD
PROCAMFramingham Classical Risk factors
0
025
05
075
1
10 105 11 115 12 125 13 135
Risk Score
Pro
ba
bil
ity
no CHD CHD Set Specificity at
5 False Positive
in no-CAD
11 of men who get
CAD have baseline
score over cut-off
89 of the events that occurred over 10 years
would not be predicted by the score
Can we improve on this with genotypes
Whıch genes
to study
20
Genotype - smoking interactions
in risk score
Better than classical +
genotypes plt00001
Adding Environment-Genotype interactions
enhances (DOUBLES) risk prediction score
0
02
04
06
6 7 8 9 10 11 12
Risk score
pro
bab
ilit
y
no CHD CHD
EVEN BETTER
24 of cases
have score
over cut-off
5 FPR
Classical Risk factors + Genotypes + Smokıng
22
2001
Cui Y Wei QQ Park HK amp Lieber CM Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species Science 293 1289ndash1292 (2001)
ldquoDevices based on nanowires are emerging as a powerful platform for the direct detection of biological and chemical species including low concentrations of proteins and virusesrdquo 1st July 2006 Analytic Chemistry
No
rma
lise
d
con
du
ctan
ce c
han
ge
Figure 18 | taken from E Stern JF Klemic DA Routenberg PN Wyrembak DB
Turner-Evans AD Hamilton DA LaVan TM Fahmy and MA Reed Label-free
immunodetection with CMOS-compatible semiconducting nanowires Nature 445
05498 (2007)
Born April 2014
Nanowire chip
DNA extraction
PCR
ldquoHandheldrdquo
Arrived from the engineers at A Star Singapore LAST WEEK
First cassettes Chloroquine resistant Malaria warfarin BRAF
tumour marker
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated
Lynch syndrome
Endometrial
Carcinoma
Bertha
Ted
3 CRC
9 skin
cancers
Family from which DNA used to Demonstrate hMSH2 mutation by Kolodnerrsquos group 1993 1st of the MISMATCH REPAIR GENE DEFECTS
Muir Torre syndrome A sub type of Lynch syndrome
ndash Microsatellites are lengths of short repeated sequences usually
ndash mononucleotides eg BAT25
tgttttgtttttttgatttttttttttttttttttttttttgagaacagagca
ndash or dinucleotides eg D5S346
aatttacacacacacacacacacacacacacacagagta
Microsatellites
600mg aspirinday for 2 yrs reduced Lynch syndrome cancers at 5 yrs
by over 50
Lancet volume 378 December 11th 2011
CAPP2 follow up data May 2013
30
10
40
20
45434
25427
12 years New colorectal cancers in blinded recruits treated for mean 25 yrs with 600mg Aspirin (green) or placebo (red) Unpublished data
= Washington University
Genome Sequencing Center
Baylor College of Medicine
Human Genome Sequencing Center
Using AB 3730 XL
fluorescent Sanger chemistry
on capillary sequencers
per month
Sequencing 2005
Next-generation sequencers
Slide courtesy of
John D McPherson OICR
Sequencing Now
First woman sequenced June 2008
Human amp Clinical Genetics
Marjolein Kriek PhD clinical geneticist
34
ldquoMan takes one step towards understanding womanrdquo
Human Genomics Strategy Group bull Government response
ndash 100000 whole genomes ndash pound100 million investment ndash Genomics Strategy Board
(NHS now HEE)
Newcastle one of four pilot centres 209743 rare disease samples (130114)
3 million
Error rates inadequate depth of coverage
copy number variation imprinted genes
splice variants
W hole genome sequencing
Functional classification of JDW SNPs
SNP Type Known SNPs Novel SNPs
Missense 8967 2421
Nonsense 44 5
Synonymous 9121 2261
UTR 18517 7102
Intron 922048 381924
August 2010 China National Highway 110 traffic jam China worldrsquos worst
traffic jam everhellip
more than 100 kilometres from August 14 - 26 inc at least 11 days of total
gridlock
We are heading for the biggest traffic jam in history
Hereditary colorectal cancer Should I request colonoscopy
Donna-Marie Ian
25 24
Positive FH
MSI high tumour
MLH1 leu559arg
Missense
Not inherited
Robert Hofstra
Rolf Sijmons
Westernno expression
Pulldown no interaction
MAPP-MMR and SIFT v2
Suggest pathogenic
Polyphen inconclusive
Reported Belvederesi EJHG
2006
Grantham Variation (GV) and Deviation (GD)
C
P
V Grantham R Science 185 862-864 1974
Tavtigian et al JMG 43 295 2006
GV
GD
HVP4 UNESCO Headquarters Paris 11-15 June 2012
Estimates of Heritability
Disorder Frequency () ()
bull Schizophrenia 1 85
bull Asthma 4 80
bull Ankylosing spondylitis 02 70
bull Neural tube defects 02 60
bull Congenital heart disease 05 60
21
bull Paper by Galton
ldquoChildren regress to
Mediocrityrdquo
Imagine if there were only 2 genes for height each with only 2 alleles H or T of equal
frequency
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
10
We discover one of the genes and call it BYH1 somebody would suggest using it for disease
prediction
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
average short Very
short tall
Very
tall
Always bump
your head
Often bump
Your head
ldquohundreds of variants in at least 180 loci influence human heightrdquo
Nature 2010 Oct 14467(7317)832-8 doi 101038nature09410 Epub 2010 Sep 29 Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen H1 Estrada K Lettre G Berndt SI Weedon MN Rivadeneira F Willer CJ Jackson AU Vedantam S Raychaudhuri S Ferreira T Wood AR Weyant RJ Segregrave AV Speliotes EK Wheeler E Soranzo N Park JH Yang J Gudbjartsson D Heard-Costa NL Randall JC Qi L Vernon Smith A Maumlgi R Pastinen T Liang L Heid IM Luan J Thorleifsson G Winkler TW Goddard ME Sin Lo K Palmer C Workalemahu T Aulchenko YS Johansson A Zillikens MC Feitosa MF Esko T Johnson T Ketkar S Kraft P Mangino M Prokopenko I Absher D Albrecht E Ernst F Glazer NL Hayward C Hottenga JJ Jacobs KB Knowles JW Kutalik Z Monda KL Polasek O Preuss M Rayner NW Robertson NR Steinthorsdottir V Tyrer JP Voight BF Wiklund F Xu J Zhao JH Nyholt DR Pellikka N Perola M Perry JR Surakka I Tammesoo ML Altmaier EL Amin N Aspelund T Bhangale T Boucher G Chasman DI Chen C Coin L Cooper MN Dixon AL Gibson Q Grundberg E Hao K Juhani Junttila M Kaplan LM Kettunen J Koumlnig IR Kwan T Lawrence RW Levinson DF Lorentzon M McKnight B Morris AP Muumlller M Suh Ngwa J Purcell S Rafelt S Salem RM Salvi E Sanna S Shi J Sovio U Thompson JR Turchin MC Vandenput L Verlaan DJ Vitart V White CC Ziegler A Almgren P Balmforth AJ Campbell H Citterio L De Grandi A Dominiczak A Duan J Elliott P Elosua R Eriksson JG Freimer NB Geus EJ Glorioso N Haiqing S Hartikainen AL Havulinna AS Hicks AA Hui J Igl W Illig T Jula A Kajantie E Kilpelaumlinen TO Koiranen M Kolcic I Koskinen S Kovacs P Laitinen J Liu J Lokki ML Marusic A Maschio A Meitinger T Mulas A Pareacute G Parker AN Peden JF Petersmann A Pichler I Pietilaumlinen KH Pouta A Ridderstraringle M Rotter JI Sambrook JG Sanders AR Schmidt CO Sinisalo J Smit JH Stringham HM Bragi Walters G Widen E Wild SH Willemsen G Zagato L Zgaga L Zitting P Alavere H Farrall M McArdle WL Nelis M Peters MJ Ripatti S van Meurs JB Aben KK Ardlie KG Beckmann JS Beilby JP Bergman RN Bergmann S Collins FS Cusi D den Heijer M Eiriksdottir G Gejman PV Hall AS Hamsten A Huikuri HV Iribarren C Kaumlhoumlnen M Kaprio J Kathiresan S Kiemeney L Kocher T Launer LJ Lehtimaumlki T Melander O Mosley TH Jr Musk AW Nieminen MS ODonnell CJ Ohlsson C Oostra B Palmer LJ Raitakari O Ridker PM Rioux JD Rissanen A Rivolta C Schunkert H Shuldiner AR Siscovick DS Stumvoll M Toumlnjes A Tuomilehto J van Ommen GJ Viikari J Heath AC Martin NG Montgomery GW Province MA Kayser M Arnold AM Atwood LD Boerwinkle E Chanock SJ Deloukas P Gieger C Groumlnberg H Hall P Hattersley AT Hengstenberg C Hoffman W Lathrop GM Salomaa V Schreiber S Uda M Waterworth D Wright AF Assimes TL Barroso I Hofman A Mohlke KL Boomsma DI Caulfield MJ Cupples LA Erdmann J Fox CS Gudnason V Gyllensten U Harris TB Hayes RB Jarvelin MR Mooser V Munroe PB Ouwehand WH Penninx BW Pramstaller PP Quertermous T Rudan I Samani NJ Spector TD Voumllzke H Watkins H Wilson JF Groop LC Haritunians T Hu FB Kaplan RC Metspalu A North KE Schlessinger D Wareham NJ Hunter DJ OConnell JR Strachan DP Wichmann HE Borecki IB van Duijn CM Schadt EE Thorsteinsdottir U Peltonen L Uitterlinden AG Visscher PM Chatterjee N Loos RJ Boehnke M McCarthy MI Ingelsson E Lindgren CM Abecasis GR Stefansson K Frayling TM Hirschhorn JN
Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen et alNature 2010 Oct 14467(7317)832-8
RISK SCORE METHOD
PROCAMFramingham Classical Risk factors
0
025
05
075
1
10 105 11 115 12 125 13 135
Risk Score
Pro
ba
bil
ity
no CHD CHD Set Specificity at
5 False Positive
in no-CAD
11 of men who get
CAD have baseline
score over cut-off
89 of the events that occurred over 10 years
would not be predicted by the score
Can we improve on this with genotypes
Whıch genes
to study
20
Genotype - smoking interactions
in risk score
Better than classical +
genotypes plt00001
Adding Environment-Genotype interactions
enhances (DOUBLES) risk prediction score
0
02
04
06
6 7 8 9 10 11 12
Risk score
pro
bab
ilit
y
no CHD CHD
EVEN BETTER
24 of cases
have score
over cut-off
5 FPR
Classical Risk factors + Genotypes + Smokıng
22
2001
Cui Y Wei QQ Park HK amp Lieber CM Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species Science 293 1289ndash1292 (2001)
ldquoDevices based on nanowires are emerging as a powerful platform for the direct detection of biological and chemical species including low concentrations of proteins and virusesrdquo 1st July 2006 Analytic Chemistry
No
rma
lise
d
con
du
ctan
ce c
han
ge
Figure 18 | taken from E Stern JF Klemic DA Routenberg PN Wyrembak DB
Turner-Evans AD Hamilton DA LaVan TM Fahmy and MA Reed Label-free
immunodetection with CMOS-compatible semiconducting nanowires Nature 445
05498 (2007)
Born April 2014
Nanowire chip
DNA extraction
PCR
ldquoHandheldrdquo
Arrived from the engineers at A Star Singapore LAST WEEK
First cassettes Chloroquine resistant Malaria warfarin BRAF
tumour marker
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated
ndash Microsatellites are lengths of short repeated sequences usually
ndash mononucleotides eg BAT25
tgttttgtttttttgatttttttttttttttttttttttttgagaacagagca
ndash or dinucleotides eg D5S346
aatttacacacacacacacacacacacacacacagagta
Microsatellites
600mg aspirinday for 2 yrs reduced Lynch syndrome cancers at 5 yrs
by over 50
Lancet volume 378 December 11th 2011
CAPP2 follow up data May 2013
30
10
40
20
45434
25427
12 years New colorectal cancers in blinded recruits treated for mean 25 yrs with 600mg Aspirin (green) or placebo (red) Unpublished data
= Washington University
Genome Sequencing Center
Baylor College of Medicine
Human Genome Sequencing Center
Using AB 3730 XL
fluorescent Sanger chemistry
on capillary sequencers
per month
Sequencing 2005
Next-generation sequencers
Slide courtesy of
John D McPherson OICR
Sequencing Now
First woman sequenced June 2008
Human amp Clinical Genetics
Marjolein Kriek PhD clinical geneticist
34
ldquoMan takes one step towards understanding womanrdquo
Human Genomics Strategy Group bull Government response
ndash 100000 whole genomes ndash pound100 million investment ndash Genomics Strategy Board
(NHS now HEE)
Newcastle one of four pilot centres 209743 rare disease samples (130114)
3 million
Error rates inadequate depth of coverage
copy number variation imprinted genes
splice variants
W hole genome sequencing
Functional classification of JDW SNPs
SNP Type Known SNPs Novel SNPs
Missense 8967 2421
Nonsense 44 5
Synonymous 9121 2261
UTR 18517 7102
Intron 922048 381924
August 2010 China National Highway 110 traffic jam China worldrsquos worst
traffic jam everhellip
more than 100 kilometres from August 14 - 26 inc at least 11 days of total
gridlock
We are heading for the biggest traffic jam in history
Hereditary colorectal cancer Should I request colonoscopy
Donna-Marie Ian
25 24
Positive FH
MSI high tumour
MLH1 leu559arg
Missense
Not inherited
Robert Hofstra
Rolf Sijmons
Westernno expression
Pulldown no interaction
MAPP-MMR and SIFT v2
Suggest pathogenic
Polyphen inconclusive
Reported Belvederesi EJHG
2006
Grantham Variation (GV) and Deviation (GD)
C
P
V Grantham R Science 185 862-864 1974
Tavtigian et al JMG 43 295 2006
GV
GD
HVP4 UNESCO Headquarters Paris 11-15 June 2012
Estimates of Heritability
Disorder Frequency () ()
bull Schizophrenia 1 85
bull Asthma 4 80
bull Ankylosing spondylitis 02 70
bull Neural tube defects 02 60
bull Congenital heart disease 05 60
21
bull Paper by Galton
ldquoChildren regress to
Mediocrityrdquo
Imagine if there were only 2 genes for height each with only 2 alleles H or T of equal
frequency
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
10
We discover one of the genes and call it BYH1 somebody would suggest using it for disease
prediction
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
average short Very
short tall
Very
tall
Always bump
your head
Often bump
Your head
ldquohundreds of variants in at least 180 loci influence human heightrdquo
Nature 2010 Oct 14467(7317)832-8 doi 101038nature09410 Epub 2010 Sep 29 Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen H1 Estrada K Lettre G Berndt SI Weedon MN Rivadeneira F Willer CJ Jackson AU Vedantam S Raychaudhuri S Ferreira T Wood AR Weyant RJ Segregrave AV Speliotes EK Wheeler E Soranzo N Park JH Yang J Gudbjartsson D Heard-Costa NL Randall JC Qi L Vernon Smith A Maumlgi R Pastinen T Liang L Heid IM Luan J Thorleifsson G Winkler TW Goddard ME Sin Lo K Palmer C Workalemahu T Aulchenko YS Johansson A Zillikens MC Feitosa MF Esko T Johnson T Ketkar S Kraft P Mangino M Prokopenko I Absher D Albrecht E Ernst F Glazer NL Hayward C Hottenga JJ Jacobs KB Knowles JW Kutalik Z Monda KL Polasek O Preuss M Rayner NW Robertson NR Steinthorsdottir V Tyrer JP Voight BF Wiklund F Xu J Zhao JH Nyholt DR Pellikka N Perola M Perry JR Surakka I Tammesoo ML Altmaier EL Amin N Aspelund T Bhangale T Boucher G Chasman DI Chen C Coin L Cooper MN Dixon AL Gibson Q Grundberg E Hao K Juhani Junttila M Kaplan LM Kettunen J Koumlnig IR Kwan T Lawrence RW Levinson DF Lorentzon M McKnight B Morris AP Muumlller M Suh Ngwa J Purcell S Rafelt S Salem RM Salvi E Sanna S Shi J Sovio U Thompson JR Turchin MC Vandenput L Verlaan DJ Vitart V White CC Ziegler A Almgren P Balmforth AJ Campbell H Citterio L De Grandi A Dominiczak A Duan J Elliott P Elosua R Eriksson JG Freimer NB Geus EJ Glorioso N Haiqing S Hartikainen AL Havulinna AS Hicks AA Hui J Igl W Illig T Jula A Kajantie E Kilpelaumlinen TO Koiranen M Kolcic I Koskinen S Kovacs P Laitinen J Liu J Lokki ML Marusic A Maschio A Meitinger T Mulas A Pareacute G Parker AN Peden JF Petersmann A Pichler I Pietilaumlinen KH Pouta A Ridderstraringle M Rotter JI Sambrook JG Sanders AR Schmidt CO Sinisalo J Smit JH Stringham HM Bragi Walters G Widen E Wild SH Willemsen G Zagato L Zgaga L Zitting P Alavere H Farrall M McArdle WL Nelis M Peters MJ Ripatti S van Meurs JB Aben KK Ardlie KG Beckmann JS Beilby JP Bergman RN Bergmann S Collins FS Cusi D den Heijer M Eiriksdottir G Gejman PV Hall AS Hamsten A Huikuri HV Iribarren C Kaumlhoumlnen M Kaprio J Kathiresan S Kiemeney L Kocher T Launer LJ Lehtimaumlki T Melander O Mosley TH Jr Musk AW Nieminen MS ODonnell CJ Ohlsson C Oostra B Palmer LJ Raitakari O Ridker PM Rioux JD Rissanen A Rivolta C Schunkert H Shuldiner AR Siscovick DS Stumvoll M Toumlnjes A Tuomilehto J van Ommen GJ Viikari J Heath AC Martin NG Montgomery GW Province MA Kayser M Arnold AM Atwood LD Boerwinkle E Chanock SJ Deloukas P Gieger C Groumlnberg H Hall P Hattersley AT Hengstenberg C Hoffman W Lathrop GM Salomaa V Schreiber S Uda M Waterworth D Wright AF Assimes TL Barroso I Hofman A Mohlke KL Boomsma DI Caulfield MJ Cupples LA Erdmann J Fox CS Gudnason V Gyllensten U Harris TB Hayes RB Jarvelin MR Mooser V Munroe PB Ouwehand WH Penninx BW Pramstaller PP Quertermous T Rudan I Samani NJ Spector TD Voumllzke H Watkins H Wilson JF Groop LC Haritunians T Hu FB Kaplan RC Metspalu A North KE Schlessinger D Wareham NJ Hunter DJ OConnell JR Strachan DP Wichmann HE Borecki IB van Duijn CM Schadt EE Thorsteinsdottir U Peltonen L Uitterlinden AG Visscher PM Chatterjee N Loos RJ Boehnke M McCarthy MI Ingelsson E Lindgren CM Abecasis GR Stefansson K Frayling TM Hirschhorn JN
Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen et alNature 2010 Oct 14467(7317)832-8
RISK SCORE METHOD
PROCAMFramingham Classical Risk factors
0
025
05
075
1
10 105 11 115 12 125 13 135
Risk Score
Pro
ba
bil
ity
no CHD CHD Set Specificity at
5 False Positive
in no-CAD
11 of men who get
CAD have baseline
score over cut-off
89 of the events that occurred over 10 years
would not be predicted by the score
Can we improve on this with genotypes
Whıch genes
to study
20
Genotype - smoking interactions
in risk score
Better than classical +
genotypes plt00001
Adding Environment-Genotype interactions
enhances (DOUBLES) risk prediction score
0
02
04
06
6 7 8 9 10 11 12
Risk score
pro
bab
ilit
y
no CHD CHD
EVEN BETTER
24 of cases
have score
over cut-off
5 FPR
Classical Risk factors + Genotypes + Smokıng
22
2001
Cui Y Wei QQ Park HK amp Lieber CM Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species Science 293 1289ndash1292 (2001)
ldquoDevices based on nanowires are emerging as a powerful platform for the direct detection of biological and chemical species including low concentrations of proteins and virusesrdquo 1st July 2006 Analytic Chemistry
No
rma
lise
d
con
du
ctan
ce c
han
ge
Figure 18 | taken from E Stern JF Klemic DA Routenberg PN Wyrembak DB
Turner-Evans AD Hamilton DA LaVan TM Fahmy and MA Reed Label-free
immunodetection with CMOS-compatible semiconducting nanowires Nature 445
05498 (2007)
Born April 2014
Nanowire chip
DNA extraction
PCR
ldquoHandheldrdquo
Arrived from the engineers at A Star Singapore LAST WEEK
First cassettes Chloroquine resistant Malaria warfarin BRAF
tumour marker
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated
600mg aspirinday for 2 yrs reduced Lynch syndrome cancers at 5 yrs
by over 50
Lancet volume 378 December 11th 2011
CAPP2 follow up data May 2013
30
10
40
20
45434
25427
12 years New colorectal cancers in blinded recruits treated for mean 25 yrs with 600mg Aspirin (green) or placebo (red) Unpublished data
= Washington University
Genome Sequencing Center
Baylor College of Medicine
Human Genome Sequencing Center
Using AB 3730 XL
fluorescent Sanger chemistry
on capillary sequencers
per month
Sequencing 2005
Next-generation sequencers
Slide courtesy of
John D McPherson OICR
Sequencing Now
First woman sequenced June 2008
Human amp Clinical Genetics
Marjolein Kriek PhD clinical geneticist
34
ldquoMan takes one step towards understanding womanrdquo
Human Genomics Strategy Group bull Government response
ndash 100000 whole genomes ndash pound100 million investment ndash Genomics Strategy Board
(NHS now HEE)
Newcastle one of four pilot centres 209743 rare disease samples (130114)
3 million
Error rates inadequate depth of coverage
copy number variation imprinted genes
splice variants
W hole genome sequencing
Functional classification of JDW SNPs
SNP Type Known SNPs Novel SNPs
Missense 8967 2421
Nonsense 44 5
Synonymous 9121 2261
UTR 18517 7102
Intron 922048 381924
August 2010 China National Highway 110 traffic jam China worldrsquos worst
traffic jam everhellip
more than 100 kilometres from August 14 - 26 inc at least 11 days of total
gridlock
We are heading for the biggest traffic jam in history
Hereditary colorectal cancer Should I request colonoscopy
Donna-Marie Ian
25 24
Positive FH
MSI high tumour
MLH1 leu559arg
Missense
Not inherited
Robert Hofstra
Rolf Sijmons
Westernno expression
Pulldown no interaction
MAPP-MMR and SIFT v2
Suggest pathogenic
Polyphen inconclusive
Reported Belvederesi EJHG
2006
Grantham Variation (GV) and Deviation (GD)
C
P
V Grantham R Science 185 862-864 1974
Tavtigian et al JMG 43 295 2006
GV
GD
HVP4 UNESCO Headquarters Paris 11-15 June 2012
Estimates of Heritability
Disorder Frequency () ()
bull Schizophrenia 1 85
bull Asthma 4 80
bull Ankylosing spondylitis 02 70
bull Neural tube defects 02 60
bull Congenital heart disease 05 60
21
bull Paper by Galton
ldquoChildren regress to
Mediocrityrdquo
Imagine if there were only 2 genes for height each with only 2 alleles H or T of equal
frequency
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
10
We discover one of the genes and call it BYH1 somebody would suggest using it for disease
prediction
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
average short Very
short tall
Very
tall
Always bump
your head
Often bump
Your head
ldquohundreds of variants in at least 180 loci influence human heightrdquo
Nature 2010 Oct 14467(7317)832-8 doi 101038nature09410 Epub 2010 Sep 29 Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen H1 Estrada K Lettre G Berndt SI Weedon MN Rivadeneira F Willer CJ Jackson AU Vedantam S Raychaudhuri S Ferreira T Wood AR Weyant RJ Segregrave AV Speliotes EK Wheeler E Soranzo N Park JH Yang J Gudbjartsson D Heard-Costa NL Randall JC Qi L Vernon Smith A Maumlgi R Pastinen T Liang L Heid IM Luan J Thorleifsson G Winkler TW Goddard ME Sin Lo K Palmer C Workalemahu T Aulchenko YS Johansson A Zillikens MC Feitosa MF Esko T Johnson T Ketkar S Kraft P Mangino M Prokopenko I Absher D Albrecht E Ernst F Glazer NL Hayward C Hottenga JJ Jacobs KB Knowles JW Kutalik Z Monda KL Polasek O Preuss M Rayner NW Robertson NR Steinthorsdottir V Tyrer JP Voight BF Wiklund F Xu J Zhao JH Nyholt DR Pellikka N Perola M Perry JR Surakka I Tammesoo ML Altmaier EL Amin N Aspelund T Bhangale T Boucher G Chasman DI Chen C Coin L Cooper MN Dixon AL Gibson Q Grundberg E Hao K Juhani Junttila M Kaplan LM Kettunen J Koumlnig IR Kwan T Lawrence RW Levinson DF Lorentzon M McKnight B Morris AP Muumlller M Suh Ngwa J Purcell S Rafelt S Salem RM Salvi E Sanna S Shi J Sovio U Thompson JR Turchin MC Vandenput L Verlaan DJ Vitart V White CC Ziegler A Almgren P Balmforth AJ Campbell H Citterio L De Grandi A Dominiczak A Duan J Elliott P Elosua R Eriksson JG Freimer NB Geus EJ Glorioso N Haiqing S Hartikainen AL Havulinna AS Hicks AA Hui J Igl W Illig T Jula A Kajantie E Kilpelaumlinen TO Koiranen M Kolcic I Koskinen S Kovacs P Laitinen J Liu J Lokki ML Marusic A Maschio A Meitinger T Mulas A Pareacute G Parker AN Peden JF Petersmann A Pichler I Pietilaumlinen KH Pouta A Ridderstraringle M Rotter JI Sambrook JG Sanders AR Schmidt CO Sinisalo J Smit JH Stringham HM Bragi Walters G Widen E Wild SH Willemsen G Zagato L Zgaga L Zitting P Alavere H Farrall M McArdle WL Nelis M Peters MJ Ripatti S van Meurs JB Aben KK Ardlie KG Beckmann JS Beilby JP Bergman RN Bergmann S Collins FS Cusi D den Heijer M Eiriksdottir G Gejman PV Hall AS Hamsten A Huikuri HV Iribarren C Kaumlhoumlnen M Kaprio J Kathiresan S Kiemeney L Kocher T Launer LJ Lehtimaumlki T Melander O Mosley TH Jr Musk AW Nieminen MS ODonnell CJ Ohlsson C Oostra B Palmer LJ Raitakari O Ridker PM Rioux JD Rissanen A Rivolta C Schunkert H Shuldiner AR Siscovick DS Stumvoll M Toumlnjes A Tuomilehto J van Ommen GJ Viikari J Heath AC Martin NG Montgomery GW Province MA Kayser M Arnold AM Atwood LD Boerwinkle E Chanock SJ Deloukas P Gieger C Groumlnberg H Hall P Hattersley AT Hengstenberg C Hoffman W Lathrop GM Salomaa V Schreiber S Uda M Waterworth D Wright AF Assimes TL Barroso I Hofman A Mohlke KL Boomsma DI Caulfield MJ Cupples LA Erdmann J Fox CS Gudnason V Gyllensten U Harris TB Hayes RB Jarvelin MR Mooser V Munroe PB Ouwehand WH Penninx BW Pramstaller PP Quertermous T Rudan I Samani NJ Spector TD Voumllzke H Watkins H Wilson JF Groop LC Haritunians T Hu FB Kaplan RC Metspalu A North KE Schlessinger D Wareham NJ Hunter DJ OConnell JR Strachan DP Wichmann HE Borecki IB van Duijn CM Schadt EE Thorsteinsdottir U Peltonen L Uitterlinden AG Visscher PM Chatterjee N Loos RJ Boehnke M McCarthy MI Ingelsson E Lindgren CM Abecasis GR Stefansson K Frayling TM Hirschhorn JN
Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen et alNature 2010 Oct 14467(7317)832-8
RISK SCORE METHOD
PROCAMFramingham Classical Risk factors
0
025
05
075
1
10 105 11 115 12 125 13 135
Risk Score
Pro
ba
bil
ity
no CHD CHD Set Specificity at
5 False Positive
in no-CAD
11 of men who get
CAD have baseline
score over cut-off
89 of the events that occurred over 10 years
would not be predicted by the score
Can we improve on this with genotypes
Whıch genes
to study
20
Genotype - smoking interactions
in risk score
Better than classical +
genotypes plt00001
Adding Environment-Genotype interactions
enhances (DOUBLES) risk prediction score
0
02
04
06
6 7 8 9 10 11 12
Risk score
pro
bab
ilit
y
no CHD CHD
EVEN BETTER
24 of cases
have score
over cut-off
5 FPR
Classical Risk factors + Genotypes + Smokıng
22
2001
Cui Y Wei QQ Park HK amp Lieber CM Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species Science 293 1289ndash1292 (2001)
ldquoDevices based on nanowires are emerging as a powerful platform for the direct detection of biological and chemical species including low concentrations of proteins and virusesrdquo 1st July 2006 Analytic Chemistry
No
rma
lise
d
con
du
ctan
ce c
han
ge
Figure 18 | taken from E Stern JF Klemic DA Routenberg PN Wyrembak DB
Turner-Evans AD Hamilton DA LaVan TM Fahmy and MA Reed Label-free
immunodetection with CMOS-compatible semiconducting nanowires Nature 445
05498 (2007)
Born April 2014
Nanowire chip
DNA extraction
PCR
ldquoHandheldrdquo
Arrived from the engineers at A Star Singapore LAST WEEK
First cassettes Chloroquine resistant Malaria warfarin BRAF
tumour marker
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated
CAPP2 follow up data May 2013
30
10
40
20
45434
25427
12 years New colorectal cancers in blinded recruits treated for mean 25 yrs with 600mg Aspirin (green) or placebo (red) Unpublished data
= Washington University
Genome Sequencing Center
Baylor College of Medicine
Human Genome Sequencing Center
Using AB 3730 XL
fluorescent Sanger chemistry
on capillary sequencers
per month
Sequencing 2005
Next-generation sequencers
Slide courtesy of
John D McPherson OICR
Sequencing Now
First woman sequenced June 2008
Human amp Clinical Genetics
Marjolein Kriek PhD clinical geneticist
34
ldquoMan takes one step towards understanding womanrdquo
Human Genomics Strategy Group bull Government response
ndash 100000 whole genomes ndash pound100 million investment ndash Genomics Strategy Board
(NHS now HEE)
Newcastle one of four pilot centres 209743 rare disease samples (130114)
3 million
Error rates inadequate depth of coverage
copy number variation imprinted genes
splice variants
W hole genome sequencing
Functional classification of JDW SNPs
SNP Type Known SNPs Novel SNPs
Missense 8967 2421
Nonsense 44 5
Synonymous 9121 2261
UTR 18517 7102
Intron 922048 381924
August 2010 China National Highway 110 traffic jam China worldrsquos worst
traffic jam everhellip
more than 100 kilometres from August 14 - 26 inc at least 11 days of total
gridlock
We are heading for the biggest traffic jam in history
Hereditary colorectal cancer Should I request colonoscopy
Donna-Marie Ian
25 24
Positive FH
MSI high tumour
MLH1 leu559arg
Missense
Not inherited
Robert Hofstra
Rolf Sijmons
Westernno expression
Pulldown no interaction
MAPP-MMR and SIFT v2
Suggest pathogenic
Polyphen inconclusive
Reported Belvederesi EJHG
2006
Grantham Variation (GV) and Deviation (GD)
C
P
V Grantham R Science 185 862-864 1974
Tavtigian et al JMG 43 295 2006
GV
GD
HVP4 UNESCO Headquarters Paris 11-15 June 2012
Estimates of Heritability
Disorder Frequency () ()
bull Schizophrenia 1 85
bull Asthma 4 80
bull Ankylosing spondylitis 02 70
bull Neural tube defects 02 60
bull Congenital heart disease 05 60
21
bull Paper by Galton
ldquoChildren regress to
Mediocrityrdquo
Imagine if there were only 2 genes for height each with only 2 alleles H or T of equal
frequency
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
10
We discover one of the genes and call it BYH1 somebody would suggest using it for disease
prediction
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
average short Very
short tall
Very
tall
Always bump
your head
Often bump
Your head
ldquohundreds of variants in at least 180 loci influence human heightrdquo
Nature 2010 Oct 14467(7317)832-8 doi 101038nature09410 Epub 2010 Sep 29 Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen H1 Estrada K Lettre G Berndt SI Weedon MN Rivadeneira F Willer CJ Jackson AU Vedantam S Raychaudhuri S Ferreira T Wood AR Weyant RJ Segregrave AV Speliotes EK Wheeler E Soranzo N Park JH Yang J Gudbjartsson D Heard-Costa NL Randall JC Qi L Vernon Smith A Maumlgi R Pastinen T Liang L Heid IM Luan J Thorleifsson G Winkler TW Goddard ME Sin Lo K Palmer C Workalemahu T Aulchenko YS Johansson A Zillikens MC Feitosa MF Esko T Johnson T Ketkar S Kraft P Mangino M Prokopenko I Absher D Albrecht E Ernst F Glazer NL Hayward C Hottenga JJ Jacobs KB Knowles JW Kutalik Z Monda KL Polasek O Preuss M Rayner NW Robertson NR Steinthorsdottir V Tyrer JP Voight BF Wiklund F Xu J Zhao JH Nyholt DR Pellikka N Perola M Perry JR Surakka I Tammesoo ML Altmaier EL Amin N Aspelund T Bhangale T Boucher G Chasman DI Chen C Coin L Cooper MN Dixon AL Gibson Q Grundberg E Hao K Juhani Junttila M Kaplan LM Kettunen J Koumlnig IR Kwan T Lawrence RW Levinson DF Lorentzon M McKnight B Morris AP Muumlller M Suh Ngwa J Purcell S Rafelt S Salem RM Salvi E Sanna S Shi J Sovio U Thompson JR Turchin MC Vandenput L Verlaan DJ Vitart V White CC Ziegler A Almgren P Balmforth AJ Campbell H Citterio L De Grandi A Dominiczak A Duan J Elliott P Elosua R Eriksson JG Freimer NB Geus EJ Glorioso N Haiqing S Hartikainen AL Havulinna AS Hicks AA Hui J Igl W Illig T Jula A Kajantie E Kilpelaumlinen TO Koiranen M Kolcic I Koskinen S Kovacs P Laitinen J Liu J Lokki ML Marusic A Maschio A Meitinger T Mulas A Pareacute G Parker AN Peden JF Petersmann A Pichler I Pietilaumlinen KH Pouta A Ridderstraringle M Rotter JI Sambrook JG Sanders AR Schmidt CO Sinisalo J Smit JH Stringham HM Bragi Walters G Widen E Wild SH Willemsen G Zagato L Zgaga L Zitting P Alavere H Farrall M McArdle WL Nelis M Peters MJ Ripatti S van Meurs JB Aben KK Ardlie KG Beckmann JS Beilby JP Bergman RN Bergmann S Collins FS Cusi D den Heijer M Eiriksdottir G Gejman PV Hall AS Hamsten A Huikuri HV Iribarren C Kaumlhoumlnen M Kaprio J Kathiresan S Kiemeney L Kocher T Launer LJ Lehtimaumlki T Melander O Mosley TH Jr Musk AW Nieminen MS ODonnell CJ Ohlsson C Oostra B Palmer LJ Raitakari O Ridker PM Rioux JD Rissanen A Rivolta C Schunkert H Shuldiner AR Siscovick DS Stumvoll M Toumlnjes A Tuomilehto J van Ommen GJ Viikari J Heath AC Martin NG Montgomery GW Province MA Kayser M Arnold AM Atwood LD Boerwinkle E Chanock SJ Deloukas P Gieger C Groumlnberg H Hall P Hattersley AT Hengstenberg C Hoffman W Lathrop GM Salomaa V Schreiber S Uda M Waterworth D Wright AF Assimes TL Barroso I Hofman A Mohlke KL Boomsma DI Caulfield MJ Cupples LA Erdmann J Fox CS Gudnason V Gyllensten U Harris TB Hayes RB Jarvelin MR Mooser V Munroe PB Ouwehand WH Penninx BW Pramstaller PP Quertermous T Rudan I Samani NJ Spector TD Voumllzke H Watkins H Wilson JF Groop LC Haritunians T Hu FB Kaplan RC Metspalu A North KE Schlessinger D Wareham NJ Hunter DJ OConnell JR Strachan DP Wichmann HE Borecki IB van Duijn CM Schadt EE Thorsteinsdottir U Peltonen L Uitterlinden AG Visscher PM Chatterjee N Loos RJ Boehnke M McCarthy MI Ingelsson E Lindgren CM Abecasis GR Stefansson K Frayling TM Hirschhorn JN
Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen et alNature 2010 Oct 14467(7317)832-8
RISK SCORE METHOD
PROCAMFramingham Classical Risk factors
0
025
05
075
1
10 105 11 115 12 125 13 135
Risk Score
Pro
ba
bil
ity
no CHD CHD Set Specificity at
5 False Positive
in no-CAD
11 of men who get
CAD have baseline
score over cut-off
89 of the events that occurred over 10 years
would not be predicted by the score
Can we improve on this with genotypes
Whıch genes
to study
20
Genotype - smoking interactions
in risk score
Better than classical +
genotypes plt00001
Adding Environment-Genotype interactions
enhances (DOUBLES) risk prediction score
0
02
04
06
6 7 8 9 10 11 12
Risk score
pro
bab
ilit
y
no CHD CHD
EVEN BETTER
24 of cases
have score
over cut-off
5 FPR
Classical Risk factors + Genotypes + Smokıng
22
2001
Cui Y Wei QQ Park HK amp Lieber CM Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species Science 293 1289ndash1292 (2001)
ldquoDevices based on nanowires are emerging as a powerful platform for the direct detection of biological and chemical species including low concentrations of proteins and virusesrdquo 1st July 2006 Analytic Chemistry
No
rma
lise
d
con
du
ctan
ce c
han
ge
Figure 18 | taken from E Stern JF Klemic DA Routenberg PN Wyrembak DB
Turner-Evans AD Hamilton DA LaVan TM Fahmy and MA Reed Label-free
immunodetection with CMOS-compatible semiconducting nanowires Nature 445
05498 (2007)
Born April 2014
Nanowire chip
DNA extraction
PCR
ldquoHandheldrdquo
Arrived from the engineers at A Star Singapore LAST WEEK
First cassettes Chloroquine resistant Malaria warfarin BRAF
tumour marker
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated
= Washington University
Genome Sequencing Center
Baylor College of Medicine
Human Genome Sequencing Center
Using AB 3730 XL
fluorescent Sanger chemistry
on capillary sequencers
per month
Sequencing 2005
Next-generation sequencers
Slide courtesy of
John D McPherson OICR
Sequencing Now
First woman sequenced June 2008
Human amp Clinical Genetics
Marjolein Kriek PhD clinical geneticist
34
ldquoMan takes one step towards understanding womanrdquo
Human Genomics Strategy Group bull Government response
ndash 100000 whole genomes ndash pound100 million investment ndash Genomics Strategy Board
(NHS now HEE)
Newcastle one of four pilot centres 209743 rare disease samples (130114)
3 million
Error rates inadequate depth of coverage
copy number variation imprinted genes
splice variants
W hole genome sequencing
Functional classification of JDW SNPs
SNP Type Known SNPs Novel SNPs
Missense 8967 2421
Nonsense 44 5
Synonymous 9121 2261
UTR 18517 7102
Intron 922048 381924
August 2010 China National Highway 110 traffic jam China worldrsquos worst
traffic jam everhellip
more than 100 kilometres from August 14 - 26 inc at least 11 days of total
gridlock
We are heading for the biggest traffic jam in history
Hereditary colorectal cancer Should I request colonoscopy
Donna-Marie Ian
25 24
Positive FH
MSI high tumour
MLH1 leu559arg
Missense
Not inherited
Robert Hofstra
Rolf Sijmons
Westernno expression
Pulldown no interaction
MAPP-MMR and SIFT v2
Suggest pathogenic
Polyphen inconclusive
Reported Belvederesi EJHG
2006
Grantham Variation (GV) and Deviation (GD)
C
P
V Grantham R Science 185 862-864 1974
Tavtigian et al JMG 43 295 2006
GV
GD
HVP4 UNESCO Headquarters Paris 11-15 June 2012
Estimates of Heritability
Disorder Frequency () ()
bull Schizophrenia 1 85
bull Asthma 4 80
bull Ankylosing spondylitis 02 70
bull Neural tube defects 02 60
bull Congenital heart disease 05 60
21
bull Paper by Galton
ldquoChildren regress to
Mediocrityrdquo
Imagine if there were only 2 genes for height each with only 2 alleles H or T of equal
frequency
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
10
We discover one of the genes and call it BYH1 somebody would suggest using it for disease
prediction
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
average short Very
short tall
Very
tall
Always bump
your head
Often bump
Your head
ldquohundreds of variants in at least 180 loci influence human heightrdquo
Nature 2010 Oct 14467(7317)832-8 doi 101038nature09410 Epub 2010 Sep 29 Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen H1 Estrada K Lettre G Berndt SI Weedon MN Rivadeneira F Willer CJ Jackson AU Vedantam S Raychaudhuri S Ferreira T Wood AR Weyant RJ Segregrave AV Speliotes EK Wheeler E Soranzo N Park JH Yang J Gudbjartsson D Heard-Costa NL Randall JC Qi L Vernon Smith A Maumlgi R Pastinen T Liang L Heid IM Luan J Thorleifsson G Winkler TW Goddard ME Sin Lo K Palmer C Workalemahu T Aulchenko YS Johansson A Zillikens MC Feitosa MF Esko T Johnson T Ketkar S Kraft P Mangino M Prokopenko I Absher D Albrecht E Ernst F Glazer NL Hayward C Hottenga JJ Jacobs KB Knowles JW Kutalik Z Monda KL Polasek O Preuss M Rayner NW Robertson NR Steinthorsdottir V Tyrer JP Voight BF Wiklund F Xu J Zhao JH Nyholt DR Pellikka N Perola M Perry JR Surakka I Tammesoo ML Altmaier EL Amin N Aspelund T Bhangale T Boucher G Chasman DI Chen C Coin L Cooper MN Dixon AL Gibson Q Grundberg E Hao K Juhani Junttila M Kaplan LM Kettunen J Koumlnig IR Kwan T Lawrence RW Levinson DF Lorentzon M McKnight B Morris AP Muumlller M Suh Ngwa J Purcell S Rafelt S Salem RM Salvi E Sanna S Shi J Sovio U Thompson JR Turchin MC Vandenput L Verlaan DJ Vitart V White CC Ziegler A Almgren P Balmforth AJ Campbell H Citterio L De Grandi A Dominiczak A Duan J Elliott P Elosua R Eriksson JG Freimer NB Geus EJ Glorioso N Haiqing S Hartikainen AL Havulinna AS Hicks AA Hui J Igl W Illig T Jula A Kajantie E Kilpelaumlinen TO Koiranen M Kolcic I Koskinen S Kovacs P Laitinen J Liu J Lokki ML Marusic A Maschio A Meitinger T Mulas A Pareacute G Parker AN Peden JF Petersmann A Pichler I Pietilaumlinen KH Pouta A Ridderstraringle M Rotter JI Sambrook JG Sanders AR Schmidt CO Sinisalo J Smit JH Stringham HM Bragi Walters G Widen E Wild SH Willemsen G Zagato L Zgaga L Zitting P Alavere H Farrall M McArdle WL Nelis M Peters MJ Ripatti S van Meurs JB Aben KK Ardlie KG Beckmann JS Beilby JP Bergman RN Bergmann S Collins FS Cusi D den Heijer M Eiriksdottir G Gejman PV Hall AS Hamsten A Huikuri HV Iribarren C Kaumlhoumlnen M Kaprio J Kathiresan S Kiemeney L Kocher T Launer LJ Lehtimaumlki T Melander O Mosley TH Jr Musk AW Nieminen MS ODonnell CJ Ohlsson C Oostra B Palmer LJ Raitakari O Ridker PM Rioux JD Rissanen A Rivolta C Schunkert H Shuldiner AR Siscovick DS Stumvoll M Toumlnjes A Tuomilehto J van Ommen GJ Viikari J Heath AC Martin NG Montgomery GW Province MA Kayser M Arnold AM Atwood LD Boerwinkle E Chanock SJ Deloukas P Gieger C Groumlnberg H Hall P Hattersley AT Hengstenberg C Hoffman W Lathrop GM Salomaa V Schreiber S Uda M Waterworth D Wright AF Assimes TL Barroso I Hofman A Mohlke KL Boomsma DI Caulfield MJ Cupples LA Erdmann J Fox CS Gudnason V Gyllensten U Harris TB Hayes RB Jarvelin MR Mooser V Munroe PB Ouwehand WH Penninx BW Pramstaller PP Quertermous T Rudan I Samani NJ Spector TD Voumllzke H Watkins H Wilson JF Groop LC Haritunians T Hu FB Kaplan RC Metspalu A North KE Schlessinger D Wareham NJ Hunter DJ OConnell JR Strachan DP Wichmann HE Borecki IB van Duijn CM Schadt EE Thorsteinsdottir U Peltonen L Uitterlinden AG Visscher PM Chatterjee N Loos RJ Boehnke M McCarthy MI Ingelsson E Lindgren CM Abecasis GR Stefansson K Frayling TM Hirschhorn JN
Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen et alNature 2010 Oct 14467(7317)832-8
RISK SCORE METHOD
PROCAMFramingham Classical Risk factors
0
025
05
075
1
10 105 11 115 12 125 13 135
Risk Score
Pro
ba
bil
ity
no CHD CHD Set Specificity at
5 False Positive
in no-CAD
11 of men who get
CAD have baseline
score over cut-off
89 of the events that occurred over 10 years
would not be predicted by the score
Can we improve on this with genotypes
Whıch genes
to study
20
Genotype - smoking interactions
in risk score
Better than classical +
genotypes plt00001
Adding Environment-Genotype interactions
enhances (DOUBLES) risk prediction score
0
02
04
06
6 7 8 9 10 11 12
Risk score
pro
bab
ilit
y
no CHD CHD
EVEN BETTER
24 of cases
have score
over cut-off
5 FPR
Classical Risk factors + Genotypes + Smokıng
22
2001
Cui Y Wei QQ Park HK amp Lieber CM Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species Science 293 1289ndash1292 (2001)
ldquoDevices based on nanowires are emerging as a powerful platform for the direct detection of biological and chemical species including low concentrations of proteins and virusesrdquo 1st July 2006 Analytic Chemistry
No
rma
lise
d
con
du
ctan
ce c
han
ge
Figure 18 | taken from E Stern JF Klemic DA Routenberg PN Wyrembak DB
Turner-Evans AD Hamilton DA LaVan TM Fahmy and MA Reed Label-free
immunodetection with CMOS-compatible semiconducting nanowires Nature 445
05498 (2007)
Born April 2014
Nanowire chip
DNA extraction
PCR
ldquoHandheldrdquo
Arrived from the engineers at A Star Singapore LAST WEEK
First cassettes Chloroquine resistant Malaria warfarin BRAF
tumour marker
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated
First woman sequenced June 2008
Human amp Clinical Genetics
Marjolein Kriek PhD clinical geneticist
34
ldquoMan takes one step towards understanding womanrdquo
Human Genomics Strategy Group bull Government response
ndash 100000 whole genomes ndash pound100 million investment ndash Genomics Strategy Board
(NHS now HEE)
Newcastle one of four pilot centres 209743 rare disease samples (130114)
3 million
Error rates inadequate depth of coverage
copy number variation imprinted genes
splice variants
W hole genome sequencing
Functional classification of JDW SNPs
SNP Type Known SNPs Novel SNPs
Missense 8967 2421
Nonsense 44 5
Synonymous 9121 2261
UTR 18517 7102
Intron 922048 381924
August 2010 China National Highway 110 traffic jam China worldrsquos worst
traffic jam everhellip
more than 100 kilometres from August 14 - 26 inc at least 11 days of total
gridlock
We are heading for the biggest traffic jam in history
Hereditary colorectal cancer Should I request colonoscopy
Donna-Marie Ian
25 24
Positive FH
MSI high tumour
MLH1 leu559arg
Missense
Not inherited
Robert Hofstra
Rolf Sijmons
Westernno expression
Pulldown no interaction
MAPP-MMR and SIFT v2
Suggest pathogenic
Polyphen inconclusive
Reported Belvederesi EJHG
2006
Grantham Variation (GV) and Deviation (GD)
C
P
V Grantham R Science 185 862-864 1974
Tavtigian et al JMG 43 295 2006
GV
GD
HVP4 UNESCO Headquarters Paris 11-15 June 2012
Estimates of Heritability
Disorder Frequency () ()
bull Schizophrenia 1 85
bull Asthma 4 80
bull Ankylosing spondylitis 02 70
bull Neural tube defects 02 60
bull Congenital heart disease 05 60
21
bull Paper by Galton
ldquoChildren regress to
Mediocrityrdquo
Imagine if there were only 2 genes for height each with only 2 alleles H or T of equal
frequency
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
10
We discover one of the genes and call it BYH1 somebody would suggest using it for disease
prediction
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
average short Very
short tall
Very
tall
Always bump
your head
Often bump
Your head
ldquohundreds of variants in at least 180 loci influence human heightrdquo
Nature 2010 Oct 14467(7317)832-8 doi 101038nature09410 Epub 2010 Sep 29 Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen H1 Estrada K Lettre G Berndt SI Weedon MN Rivadeneira F Willer CJ Jackson AU Vedantam S Raychaudhuri S Ferreira T Wood AR Weyant RJ Segregrave AV Speliotes EK Wheeler E Soranzo N Park JH Yang J Gudbjartsson D Heard-Costa NL Randall JC Qi L Vernon Smith A Maumlgi R Pastinen T Liang L Heid IM Luan J Thorleifsson G Winkler TW Goddard ME Sin Lo K Palmer C Workalemahu T Aulchenko YS Johansson A Zillikens MC Feitosa MF Esko T Johnson T Ketkar S Kraft P Mangino M Prokopenko I Absher D Albrecht E Ernst F Glazer NL Hayward C Hottenga JJ Jacobs KB Knowles JW Kutalik Z Monda KL Polasek O Preuss M Rayner NW Robertson NR Steinthorsdottir V Tyrer JP Voight BF Wiklund F Xu J Zhao JH Nyholt DR Pellikka N Perola M Perry JR Surakka I Tammesoo ML Altmaier EL Amin N Aspelund T Bhangale T Boucher G Chasman DI Chen C Coin L Cooper MN Dixon AL Gibson Q Grundberg E Hao K Juhani Junttila M Kaplan LM Kettunen J Koumlnig IR Kwan T Lawrence RW Levinson DF Lorentzon M McKnight B Morris AP Muumlller M Suh Ngwa J Purcell S Rafelt S Salem RM Salvi E Sanna S Shi J Sovio U Thompson JR Turchin MC Vandenput L Verlaan DJ Vitart V White CC Ziegler A Almgren P Balmforth AJ Campbell H Citterio L De Grandi A Dominiczak A Duan J Elliott P Elosua R Eriksson JG Freimer NB Geus EJ Glorioso N Haiqing S Hartikainen AL Havulinna AS Hicks AA Hui J Igl W Illig T Jula A Kajantie E Kilpelaumlinen TO Koiranen M Kolcic I Koskinen S Kovacs P Laitinen J Liu J Lokki ML Marusic A Maschio A Meitinger T Mulas A Pareacute G Parker AN Peden JF Petersmann A Pichler I Pietilaumlinen KH Pouta A Ridderstraringle M Rotter JI Sambrook JG Sanders AR Schmidt CO Sinisalo J Smit JH Stringham HM Bragi Walters G Widen E Wild SH Willemsen G Zagato L Zgaga L Zitting P Alavere H Farrall M McArdle WL Nelis M Peters MJ Ripatti S van Meurs JB Aben KK Ardlie KG Beckmann JS Beilby JP Bergman RN Bergmann S Collins FS Cusi D den Heijer M Eiriksdottir G Gejman PV Hall AS Hamsten A Huikuri HV Iribarren C Kaumlhoumlnen M Kaprio J Kathiresan S Kiemeney L Kocher T Launer LJ Lehtimaumlki T Melander O Mosley TH Jr Musk AW Nieminen MS ODonnell CJ Ohlsson C Oostra B Palmer LJ Raitakari O Ridker PM Rioux JD Rissanen A Rivolta C Schunkert H Shuldiner AR Siscovick DS Stumvoll M Toumlnjes A Tuomilehto J van Ommen GJ Viikari J Heath AC Martin NG Montgomery GW Province MA Kayser M Arnold AM Atwood LD Boerwinkle E Chanock SJ Deloukas P Gieger C Groumlnberg H Hall P Hattersley AT Hengstenberg C Hoffman W Lathrop GM Salomaa V Schreiber S Uda M Waterworth D Wright AF Assimes TL Barroso I Hofman A Mohlke KL Boomsma DI Caulfield MJ Cupples LA Erdmann J Fox CS Gudnason V Gyllensten U Harris TB Hayes RB Jarvelin MR Mooser V Munroe PB Ouwehand WH Penninx BW Pramstaller PP Quertermous T Rudan I Samani NJ Spector TD Voumllzke H Watkins H Wilson JF Groop LC Haritunians T Hu FB Kaplan RC Metspalu A North KE Schlessinger D Wareham NJ Hunter DJ OConnell JR Strachan DP Wichmann HE Borecki IB van Duijn CM Schadt EE Thorsteinsdottir U Peltonen L Uitterlinden AG Visscher PM Chatterjee N Loos RJ Boehnke M McCarthy MI Ingelsson E Lindgren CM Abecasis GR Stefansson K Frayling TM Hirschhorn JN
Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen et alNature 2010 Oct 14467(7317)832-8
RISK SCORE METHOD
PROCAMFramingham Classical Risk factors
0
025
05
075
1
10 105 11 115 12 125 13 135
Risk Score
Pro
ba
bil
ity
no CHD CHD Set Specificity at
5 False Positive
in no-CAD
11 of men who get
CAD have baseline
score over cut-off
89 of the events that occurred over 10 years
would not be predicted by the score
Can we improve on this with genotypes
Whıch genes
to study
20
Genotype - smoking interactions
in risk score
Better than classical +
genotypes plt00001
Adding Environment-Genotype interactions
enhances (DOUBLES) risk prediction score
0
02
04
06
6 7 8 9 10 11 12
Risk score
pro
bab
ilit
y
no CHD CHD
EVEN BETTER
24 of cases
have score
over cut-off
5 FPR
Classical Risk factors + Genotypes + Smokıng
22
2001
Cui Y Wei QQ Park HK amp Lieber CM Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species Science 293 1289ndash1292 (2001)
ldquoDevices based on nanowires are emerging as a powerful platform for the direct detection of biological and chemical species including low concentrations of proteins and virusesrdquo 1st July 2006 Analytic Chemistry
No
rma
lise
d
con
du
ctan
ce c
han
ge
Figure 18 | taken from E Stern JF Klemic DA Routenberg PN Wyrembak DB
Turner-Evans AD Hamilton DA LaVan TM Fahmy and MA Reed Label-free
immunodetection with CMOS-compatible semiconducting nanowires Nature 445
05498 (2007)
Born April 2014
Nanowire chip
DNA extraction
PCR
ldquoHandheldrdquo
Arrived from the engineers at A Star Singapore LAST WEEK
First cassettes Chloroquine resistant Malaria warfarin BRAF
tumour marker
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated
Human Genomics Strategy Group bull Government response
ndash 100000 whole genomes ndash pound100 million investment ndash Genomics Strategy Board
(NHS now HEE)
Newcastle one of four pilot centres 209743 rare disease samples (130114)
3 million
Error rates inadequate depth of coverage
copy number variation imprinted genes
splice variants
W hole genome sequencing
Functional classification of JDW SNPs
SNP Type Known SNPs Novel SNPs
Missense 8967 2421
Nonsense 44 5
Synonymous 9121 2261
UTR 18517 7102
Intron 922048 381924
August 2010 China National Highway 110 traffic jam China worldrsquos worst
traffic jam everhellip
more than 100 kilometres from August 14 - 26 inc at least 11 days of total
gridlock
We are heading for the biggest traffic jam in history
Hereditary colorectal cancer Should I request colonoscopy
Donna-Marie Ian
25 24
Positive FH
MSI high tumour
MLH1 leu559arg
Missense
Not inherited
Robert Hofstra
Rolf Sijmons
Westernno expression
Pulldown no interaction
MAPP-MMR and SIFT v2
Suggest pathogenic
Polyphen inconclusive
Reported Belvederesi EJHG
2006
Grantham Variation (GV) and Deviation (GD)
C
P
V Grantham R Science 185 862-864 1974
Tavtigian et al JMG 43 295 2006
GV
GD
HVP4 UNESCO Headquarters Paris 11-15 June 2012
Estimates of Heritability
Disorder Frequency () ()
bull Schizophrenia 1 85
bull Asthma 4 80
bull Ankylosing spondylitis 02 70
bull Neural tube defects 02 60
bull Congenital heart disease 05 60
21
bull Paper by Galton
ldquoChildren regress to
Mediocrityrdquo
Imagine if there were only 2 genes for height each with only 2 alleles H or T of equal
frequency
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
10
We discover one of the genes and call it BYH1 somebody would suggest using it for disease
prediction
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
average short Very
short tall
Very
tall
Always bump
your head
Often bump
Your head
ldquohundreds of variants in at least 180 loci influence human heightrdquo
Nature 2010 Oct 14467(7317)832-8 doi 101038nature09410 Epub 2010 Sep 29 Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen H1 Estrada K Lettre G Berndt SI Weedon MN Rivadeneira F Willer CJ Jackson AU Vedantam S Raychaudhuri S Ferreira T Wood AR Weyant RJ Segregrave AV Speliotes EK Wheeler E Soranzo N Park JH Yang J Gudbjartsson D Heard-Costa NL Randall JC Qi L Vernon Smith A Maumlgi R Pastinen T Liang L Heid IM Luan J Thorleifsson G Winkler TW Goddard ME Sin Lo K Palmer C Workalemahu T Aulchenko YS Johansson A Zillikens MC Feitosa MF Esko T Johnson T Ketkar S Kraft P Mangino M Prokopenko I Absher D Albrecht E Ernst F Glazer NL Hayward C Hottenga JJ Jacobs KB Knowles JW Kutalik Z Monda KL Polasek O Preuss M Rayner NW Robertson NR Steinthorsdottir V Tyrer JP Voight BF Wiklund F Xu J Zhao JH Nyholt DR Pellikka N Perola M Perry JR Surakka I Tammesoo ML Altmaier EL Amin N Aspelund T Bhangale T Boucher G Chasman DI Chen C Coin L Cooper MN Dixon AL Gibson Q Grundberg E Hao K Juhani Junttila M Kaplan LM Kettunen J Koumlnig IR Kwan T Lawrence RW Levinson DF Lorentzon M McKnight B Morris AP Muumlller M Suh Ngwa J Purcell S Rafelt S Salem RM Salvi E Sanna S Shi J Sovio U Thompson JR Turchin MC Vandenput L Verlaan DJ Vitart V White CC Ziegler A Almgren P Balmforth AJ Campbell H Citterio L De Grandi A Dominiczak A Duan J Elliott P Elosua R Eriksson JG Freimer NB Geus EJ Glorioso N Haiqing S Hartikainen AL Havulinna AS Hicks AA Hui J Igl W Illig T Jula A Kajantie E Kilpelaumlinen TO Koiranen M Kolcic I Koskinen S Kovacs P Laitinen J Liu J Lokki ML Marusic A Maschio A Meitinger T Mulas A Pareacute G Parker AN Peden JF Petersmann A Pichler I Pietilaumlinen KH Pouta A Ridderstraringle M Rotter JI Sambrook JG Sanders AR Schmidt CO Sinisalo J Smit JH Stringham HM Bragi Walters G Widen E Wild SH Willemsen G Zagato L Zgaga L Zitting P Alavere H Farrall M McArdle WL Nelis M Peters MJ Ripatti S van Meurs JB Aben KK Ardlie KG Beckmann JS Beilby JP Bergman RN Bergmann S Collins FS Cusi D den Heijer M Eiriksdottir G Gejman PV Hall AS Hamsten A Huikuri HV Iribarren C Kaumlhoumlnen M Kaprio J Kathiresan S Kiemeney L Kocher T Launer LJ Lehtimaumlki T Melander O Mosley TH Jr Musk AW Nieminen MS ODonnell CJ Ohlsson C Oostra B Palmer LJ Raitakari O Ridker PM Rioux JD Rissanen A Rivolta C Schunkert H Shuldiner AR Siscovick DS Stumvoll M Toumlnjes A Tuomilehto J van Ommen GJ Viikari J Heath AC Martin NG Montgomery GW Province MA Kayser M Arnold AM Atwood LD Boerwinkle E Chanock SJ Deloukas P Gieger C Groumlnberg H Hall P Hattersley AT Hengstenberg C Hoffman W Lathrop GM Salomaa V Schreiber S Uda M Waterworth D Wright AF Assimes TL Barroso I Hofman A Mohlke KL Boomsma DI Caulfield MJ Cupples LA Erdmann J Fox CS Gudnason V Gyllensten U Harris TB Hayes RB Jarvelin MR Mooser V Munroe PB Ouwehand WH Penninx BW Pramstaller PP Quertermous T Rudan I Samani NJ Spector TD Voumllzke H Watkins H Wilson JF Groop LC Haritunians T Hu FB Kaplan RC Metspalu A North KE Schlessinger D Wareham NJ Hunter DJ OConnell JR Strachan DP Wichmann HE Borecki IB van Duijn CM Schadt EE Thorsteinsdottir U Peltonen L Uitterlinden AG Visscher PM Chatterjee N Loos RJ Boehnke M McCarthy MI Ingelsson E Lindgren CM Abecasis GR Stefansson K Frayling TM Hirschhorn JN
Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen et alNature 2010 Oct 14467(7317)832-8
RISK SCORE METHOD
PROCAMFramingham Classical Risk factors
0
025
05
075
1
10 105 11 115 12 125 13 135
Risk Score
Pro
ba
bil
ity
no CHD CHD Set Specificity at
5 False Positive
in no-CAD
11 of men who get
CAD have baseline
score over cut-off
89 of the events that occurred over 10 years
would not be predicted by the score
Can we improve on this with genotypes
Whıch genes
to study
20
Genotype - smoking interactions
in risk score
Better than classical +
genotypes plt00001
Adding Environment-Genotype interactions
enhances (DOUBLES) risk prediction score
0
02
04
06
6 7 8 9 10 11 12
Risk score
pro
bab
ilit
y
no CHD CHD
EVEN BETTER
24 of cases
have score
over cut-off
5 FPR
Classical Risk factors + Genotypes + Smokıng
22
2001
Cui Y Wei QQ Park HK amp Lieber CM Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species Science 293 1289ndash1292 (2001)
ldquoDevices based on nanowires are emerging as a powerful platform for the direct detection of biological and chemical species including low concentrations of proteins and virusesrdquo 1st July 2006 Analytic Chemistry
No
rma
lise
d
con
du
ctan
ce c
han
ge
Figure 18 | taken from E Stern JF Klemic DA Routenberg PN Wyrembak DB
Turner-Evans AD Hamilton DA LaVan TM Fahmy and MA Reed Label-free
immunodetection with CMOS-compatible semiconducting nanowires Nature 445
05498 (2007)
Born April 2014
Nanowire chip
DNA extraction
PCR
ldquoHandheldrdquo
Arrived from the engineers at A Star Singapore LAST WEEK
First cassettes Chloroquine resistant Malaria warfarin BRAF
tumour marker
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated
3 million
Error rates inadequate depth of coverage
copy number variation imprinted genes
splice variants
W hole genome sequencing
Functional classification of JDW SNPs
SNP Type Known SNPs Novel SNPs
Missense 8967 2421
Nonsense 44 5
Synonymous 9121 2261
UTR 18517 7102
Intron 922048 381924
August 2010 China National Highway 110 traffic jam China worldrsquos worst
traffic jam everhellip
more than 100 kilometres from August 14 - 26 inc at least 11 days of total
gridlock
We are heading for the biggest traffic jam in history
Hereditary colorectal cancer Should I request colonoscopy
Donna-Marie Ian
25 24
Positive FH
MSI high tumour
MLH1 leu559arg
Missense
Not inherited
Robert Hofstra
Rolf Sijmons
Westernno expression
Pulldown no interaction
MAPP-MMR and SIFT v2
Suggest pathogenic
Polyphen inconclusive
Reported Belvederesi EJHG
2006
Grantham Variation (GV) and Deviation (GD)
C
P
V Grantham R Science 185 862-864 1974
Tavtigian et al JMG 43 295 2006
GV
GD
HVP4 UNESCO Headquarters Paris 11-15 June 2012
Estimates of Heritability
Disorder Frequency () ()
bull Schizophrenia 1 85
bull Asthma 4 80
bull Ankylosing spondylitis 02 70
bull Neural tube defects 02 60
bull Congenital heart disease 05 60
21
bull Paper by Galton
ldquoChildren regress to
Mediocrityrdquo
Imagine if there were only 2 genes for height each with only 2 alleles H or T of equal
frequency
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
10
We discover one of the genes and call it BYH1 somebody would suggest using it for disease
prediction
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
average short Very
short tall
Very
tall
Always bump
your head
Often bump
Your head
ldquohundreds of variants in at least 180 loci influence human heightrdquo
Nature 2010 Oct 14467(7317)832-8 doi 101038nature09410 Epub 2010 Sep 29 Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen H1 Estrada K Lettre G Berndt SI Weedon MN Rivadeneira F Willer CJ Jackson AU Vedantam S Raychaudhuri S Ferreira T Wood AR Weyant RJ Segregrave AV Speliotes EK Wheeler E Soranzo N Park JH Yang J Gudbjartsson D Heard-Costa NL Randall JC Qi L Vernon Smith A Maumlgi R Pastinen T Liang L Heid IM Luan J Thorleifsson G Winkler TW Goddard ME Sin Lo K Palmer C Workalemahu T Aulchenko YS Johansson A Zillikens MC Feitosa MF Esko T Johnson T Ketkar S Kraft P Mangino M Prokopenko I Absher D Albrecht E Ernst F Glazer NL Hayward C Hottenga JJ Jacobs KB Knowles JW Kutalik Z Monda KL Polasek O Preuss M Rayner NW Robertson NR Steinthorsdottir V Tyrer JP Voight BF Wiklund F Xu J Zhao JH Nyholt DR Pellikka N Perola M Perry JR Surakka I Tammesoo ML Altmaier EL Amin N Aspelund T Bhangale T Boucher G Chasman DI Chen C Coin L Cooper MN Dixon AL Gibson Q Grundberg E Hao K Juhani Junttila M Kaplan LM Kettunen J Koumlnig IR Kwan T Lawrence RW Levinson DF Lorentzon M McKnight B Morris AP Muumlller M Suh Ngwa J Purcell S Rafelt S Salem RM Salvi E Sanna S Shi J Sovio U Thompson JR Turchin MC Vandenput L Verlaan DJ Vitart V White CC Ziegler A Almgren P Balmforth AJ Campbell H Citterio L De Grandi A Dominiczak A Duan J Elliott P Elosua R Eriksson JG Freimer NB Geus EJ Glorioso N Haiqing S Hartikainen AL Havulinna AS Hicks AA Hui J Igl W Illig T Jula A Kajantie E Kilpelaumlinen TO Koiranen M Kolcic I Koskinen S Kovacs P Laitinen J Liu J Lokki ML Marusic A Maschio A Meitinger T Mulas A Pareacute G Parker AN Peden JF Petersmann A Pichler I Pietilaumlinen KH Pouta A Ridderstraringle M Rotter JI Sambrook JG Sanders AR Schmidt CO Sinisalo J Smit JH Stringham HM Bragi Walters G Widen E Wild SH Willemsen G Zagato L Zgaga L Zitting P Alavere H Farrall M McArdle WL Nelis M Peters MJ Ripatti S van Meurs JB Aben KK Ardlie KG Beckmann JS Beilby JP Bergman RN Bergmann S Collins FS Cusi D den Heijer M Eiriksdottir G Gejman PV Hall AS Hamsten A Huikuri HV Iribarren C Kaumlhoumlnen M Kaprio J Kathiresan S Kiemeney L Kocher T Launer LJ Lehtimaumlki T Melander O Mosley TH Jr Musk AW Nieminen MS ODonnell CJ Ohlsson C Oostra B Palmer LJ Raitakari O Ridker PM Rioux JD Rissanen A Rivolta C Schunkert H Shuldiner AR Siscovick DS Stumvoll M Toumlnjes A Tuomilehto J van Ommen GJ Viikari J Heath AC Martin NG Montgomery GW Province MA Kayser M Arnold AM Atwood LD Boerwinkle E Chanock SJ Deloukas P Gieger C Groumlnberg H Hall P Hattersley AT Hengstenberg C Hoffman W Lathrop GM Salomaa V Schreiber S Uda M Waterworth D Wright AF Assimes TL Barroso I Hofman A Mohlke KL Boomsma DI Caulfield MJ Cupples LA Erdmann J Fox CS Gudnason V Gyllensten U Harris TB Hayes RB Jarvelin MR Mooser V Munroe PB Ouwehand WH Penninx BW Pramstaller PP Quertermous T Rudan I Samani NJ Spector TD Voumllzke H Watkins H Wilson JF Groop LC Haritunians T Hu FB Kaplan RC Metspalu A North KE Schlessinger D Wareham NJ Hunter DJ OConnell JR Strachan DP Wichmann HE Borecki IB van Duijn CM Schadt EE Thorsteinsdottir U Peltonen L Uitterlinden AG Visscher PM Chatterjee N Loos RJ Boehnke M McCarthy MI Ingelsson E Lindgren CM Abecasis GR Stefansson K Frayling TM Hirschhorn JN
Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen et alNature 2010 Oct 14467(7317)832-8
RISK SCORE METHOD
PROCAMFramingham Classical Risk factors
0
025
05
075
1
10 105 11 115 12 125 13 135
Risk Score
Pro
ba
bil
ity
no CHD CHD Set Specificity at
5 False Positive
in no-CAD
11 of men who get
CAD have baseline
score over cut-off
89 of the events that occurred over 10 years
would not be predicted by the score
Can we improve on this with genotypes
Whıch genes
to study
20
Genotype - smoking interactions
in risk score
Better than classical +
genotypes plt00001
Adding Environment-Genotype interactions
enhances (DOUBLES) risk prediction score
0
02
04
06
6 7 8 9 10 11 12
Risk score
pro
bab
ilit
y
no CHD CHD
EVEN BETTER
24 of cases
have score
over cut-off
5 FPR
Classical Risk factors + Genotypes + Smokıng
22
2001
Cui Y Wei QQ Park HK amp Lieber CM Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species Science 293 1289ndash1292 (2001)
ldquoDevices based on nanowires are emerging as a powerful platform for the direct detection of biological and chemical species including low concentrations of proteins and virusesrdquo 1st July 2006 Analytic Chemistry
No
rma
lise
d
con
du
ctan
ce c
han
ge
Figure 18 | taken from E Stern JF Klemic DA Routenberg PN Wyrembak DB
Turner-Evans AD Hamilton DA LaVan TM Fahmy and MA Reed Label-free
immunodetection with CMOS-compatible semiconducting nanowires Nature 445
05498 (2007)
Born April 2014
Nanowire chip
DNA extraction
PCR
ldquoHandheldrdquo
Arrived from the engineers at A Star Singapore LAST WEEK
First cassettes Chloroquine resistant Malaria warfarin BRAF
tumour marker
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated
Error rates inadequate depth of coverage
copy number variation imprinted genes
splice variants
W hole genome sequencing
Functional classification of JDW SNPs
SNP Type Known SNPs Novel SNPs
Missense 8967 2421
Nonsense 44 5
Synonymous 9121 2261
UTR 18517 7102
Intron 922048 381924
August 2010 China National Highway 110 traffic jam China worldrsquos worst
traffic jam everhellip
more than 100 kilometres from August 14 - 26 inc at least 11 days of total
gridlock
We are heading for the biggest traffic jam in history
Hereditary colorectal cancer Should I request colonoscopy
Donna-Marie Ian
25 24
Positive FH
MSI high tumour
MLH1 leu559arg
Missense
Not inherited
Robert Hofstra
Rolf Sijmons
Westernno expression
Pulldown no interaction
MAPP-MMR and SIFT v2
Suggest pathogenic
Polyphen inconclusive
Reported Belvederesi EJHG
2006
Grantham Variation (GV) and Deviation (GD)
C
P
V Grantham R Science 185 862-864 1974
Tavtigian et al JMG 43 295 2006
GV
GD
HVP4 UNESCO Headquarters Paris 11-15 June 2012
Estimates of Heritability
Disorder Frequency () ()
bull Schizophrenia 1 85
bull Asthma 4 80
bull Ankylosing spondylitis 02 70
bull Neural tube defects 02 60
bull Congenital heart disease 05 60
21
bull Paper by Galton
ldquoChildren regress to
Mediocrityrdquo
Imagine if there were only 2 genes for height each with only 2 alleles H or T of equal
frequency
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
10
We discover one of the genes and call it BYH1 somebody would suggest using it for disease
prediction
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
average short Very
short tall
Very
tall
Always bump
your head
Often bump
Your head
ldquohundreds of variants in at least 180 loci influence human heightrdquo
Nature 2010 Oct 14467(7317)832-8 doi 101038nature09410 Epub 2010 Sep 29 Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen H1 Estrada K Lettre G Berndt SI Weedon MN Rivadeneira F Willer CJ Jackson AU Vedantam S Raychaudhuri S Ferreira T Wood AR Weyant RJ Segregrave AV Speliotes EK Wheeler E Soranzo N Park JH Yang J Gudbjartsson D Heard-Costa NL Randall JC Qi L Vernon Smith A Maumlgi R Pastinen T Liang L Heid IM Luan J Thorleifsson G Winkler TW Goddard ME Sin Lo K Palmer C Workalemahu T Aulchenko YS Johansson A Zillikens MC Feitosa MF Esko T Johnson T Ketkar S Kraft P Mangino M Prokopenko I Absher D Albrecht E Ernst F Glazer NL Hayward C Hottenga JJ Jacobs KB Knowles JW Kutalik Z Monda KL Polasek O Preuss M Rayner NW Robertson NR Steinthorsdottir V Tyrer JP Voight BF Wiklund F Xu J Zhao JH Nyholt DR Pellikka N Perola M Perry JR Surakka I Tammesoo ML Altmaier EL Amin N Aspelund T Bhangale T Boucher G Chasman DI Chen C Coin L Cooper MN Dixon AL Gibson Q Grundberg E Hao K Juhani Junttila M Kaplan LM Kettunen J Koumlnig IR Kwan T Lawrence RW Levinson DF Lorentzon M McKnight B Morris AP Muumlller M Suh Ngwa J Purcell S Rafelt S Salem RM Salvi E Sanna S Shi J Sovio U Thompson JR Turchin MC Vandenput L Verlaan DJ Vitart V White CC Ziegler A Almgren P Balmforth AJ Campbell H Citterio L De Grandi A Dominiczak A Duan J Elliott P Elosua R Eriksson JG Freimer NB Geus EJ Glorioso N Haiqing S Hartikainen AL Havulinna AS Hicks AA Hui J Igl W Illig T Jula A Kajantie E Kilpelaumlinen TO Koiranen M Kolcic I Koskinen S Kovacs P Laitinen J Liu J Lokki ML Marusic A Maschio A Meitinger T Mulas A Pareacute G Parker AN Peden JF Petersmann A Pichler I Pietilaumlinen KH Pouta A Ridderstraringle M Rotter JI Sambrook JG Sanders AR Schmidt CO Sinisalo J Smit JH Stringham HM Bragi Walters G Widen E Wild SH Willemsen G Zagato L Zgaga L Zitting P Alavere H Farrall M McArdle WL Nelis M Peters MJ Ripatti S van Meurs JB Aben KK Ardlie KG Beckmann JS Beilby JP Bergman RN Bergmann S Collins FS Cusi D den Heijer M Eiriksdottir G Gejman PV Hall AS Hamsten A Huikuri HV Iribarren C Kaumlhoumlnen M Kaprio J Kathiresan S Kiemeney L Kocher T Launer LJ Lehtimaumlki T Melander O Mosley TH Jr Musk AW Nieminen MS ODonnell CJ Ohlsson C Oostra B Palmer LJ Raitakari O Ridker PM Rioux JD Rissanen A Rivolta C Schunkert H Shuldiner AR Siscovick DS Stumvoll M Toumlnjes A Tuomilehto J van Ommen GJ Viikari J Heath AC Martin NG Montgomery GW Province MA Kayser M Arnold AM Atwood LD Boerwinkle E Chanock SJ Deloukas P Gieger C Groumlnberg H Hall P Hattersley AT Hengstenberg C Hoffman W Lathrop GM Salomaa V Schreiber S Uda M Waterworth D Wright AF Assimes TL Barroso I Hofman A Mohlke KL Boomsma DI Caulfield MJ Cupples LA Erdmann J Fox CS Gudnason V Gyllensten U Harris TB Hayes RB Jarvelin MR Mooser V Munroe PB Ouwehand WH Penninx BW Pramstaller PP Quertermous T Rudan I Samani NJ Spector TD Voumllzke H Watkins H Wilson JF Groop LC Haritunians T Hu FB Kaplan RC Metspalu A North KE Schlessinger D Wareham NJ Hunter DJ OConnell JR Strachan DP Wichmann HE Borecki IB van Duijn CM Schadt EE Thorsteinsdottir U Peltonen L Uitterlinden AG Visscher PM Chatterjee N Loos RJ Boehnke M McCarthy MI Ingelsson E Lindgren CM Abecasis GR Stefansson K Frayling TM Hirschhorn JN
Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen et alNature 2010 Oct 14467(7317)832-8
RISK SCORE METHOD
PROCAMFramingham Classical Risk factors
0
025
05
075
1
10 105 11 115 12 125 13 135
Risk Score
Pro
ba
bil
ity
no CHD CHD Set Specificity at
5 False Positive
in no-CAD
11 of men who get
CAD have baseline
score over cut-off
89 of the events that occurred over 10 years
would not be predicted by the score
Can we improve on this with genotypes
Whıch genes
to study
20
Genotype - smoking interactions
in risk score
Better than classical +
genotypes plt00001
Adding Environment-Genotype interactions
enhances (DOUBLES) risk prediction score
0
02
04
06
6 7 8 9 10 11 12
Risk score
pro
bab
ilit
y
no CHD CHD
EVEN BETTER
24 of cases
have score
over cut-off
5 FPR
Classical Risk factors + Genotypes + Smokıng
22
2001
Cui Y Wei QQ Park HK amp Lieber CM Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species Science 293 1289ndash1292 (2001)
ldquoDevices based on nanowires are emerging as a powerful platform for the direct detection of biological and chemical species including low concentrations of proteins and virusesrdquo 1st July 2006 Analytic Chemistry
No
rma
lise
d
con
du
ctan
ce c
han
ge
Figure 18 | taken from E Stern JF Klemic DA Routenberg PN Wyrembak DB
Turner-Evans AD Hamilton DA LaVan TM Fahmy and MA Reed Label-free
immunodetection with CMOS-compatible semiconducting nanowires Nature 445
05498 (2007)
Born April 2014
Nanowire chip
DNA extraction
PCR
ldquoHandheldrdquo
Arrived from the engineers at A Star Singapore LAST WEEK
First cassettes Chloroquine resistant Malaria warfarin BRAF
tumour marker
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated
Functional classification of JDW SNPs
SNP Type Known SNPs Novel SNPs
Missense 8967 2421
Nonsense 44 5
Synonymous 9121 2261
UTR 18517 7102
Intron 922048 381924
August 2010 China National Highway 110 traffic jam China worldrsquos worst
traffic jam everhellip
more than 100 kilometres from August 14 - 26 inc at least 11 days of total
gridlock
We are heading for the biggest traffic jam in history
Hereditary colorectal cancer Should I request colonoscopy
Donna-Marie Ian
25 24
Positive FH
MSI high tumour
MLH1 leu559arg
Missense
Not inherited
Robert Hofstra
Rolf Sijmons
Westernno expression
Pulldown no interaction
MAPP-MMR and SIFT v2
Suggest pathogenic
Polyphen inconclusive
Reported Belvederesi EJHG
2006
Grantham Variation (GV) and Deviation (GD)
C
P
V Grantham R Science 185 862-864 1974
Tavtigian et al JMG 43 295 2006
GV
GD
HVP4 UNESCO Headquarters Paris 11-15 June 2012
Estimates of Heritability
Disorder Frequency () ()
bull Schizophrenia 1 85
bull Asthma 4 80
bull Ankylosing spondylitis 02 70
bull Neural tube defects 02 60
bull Congenital heart disease 05 60
21
bull Paper by Galton
ldquoChildren regress to
Mediocrityrdquo
Imagine if there were only 2 genes for height each with only 2 alleles H or T of equal
frequency
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
10
We discover one of the genes and call it BYH1 somebody would suggest using it for disease
prediction
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
average short Very
short tall
Very
tall
Always bump
your head
Often bump
Your head
ldquohundreds of variants in at least 180 loci influence human heightrdquo
Nature 2010 Oct 14467(7317)832-8 doi 101038nature09410 Epub 2010 Sep 29 Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen H1 Estrada K Lettre G Berndt SI Weedon MN Rivadeneira F Willer CJ Jackson AU Vedantam S Raychaudhuri S Ferreira T Wood AR Weyant RJ Segregrave AV Speliotes EK Wheeler E Soranzo N Park JH Yang J Gudbjartsson D Heard-Costa NL Randall JC Qi L Vernon Smith A Maumlgi R Pastinen T Liang L Heid IM Luan J Thorleifsson G Winkler TW Goddard ME Sin Lo K Palmer C Workalemahu T Aulchenko YS Johansson A Zillikens MC Feitosa MF Esko T Johnson T Ketkar S Kraft P Mangino M Prokopenko I Absher D Albrecht E Ernst F Glazer NL Hayward C Hottenga JJ Jacobs KB Knowles JW Kutalik Z Monda KL Polasek O Preuss M Rayner NW Robertson NR Steinthorsdottir V Tyrer JP Voight BF Wiklund F Xu J Zhao JH Nyholt DR Pellikka N Perola M Perry JR Surakka I Tammesoo ML Altmaier EL Amin N Aspelund T Bhangale T Boucher G Chasman DI Chen C Coin L Cooper MN Dixon AL Gibson Q Grundberg E Hao K Juhani Junttila M Kaplan LM Kettunen J Koumlnig IR Kwan T Lawrence RW Levinson DF Lorentzon M McKnight B Morris AP Muumlller M Suh Ngwa J Purcell S Rafelt S Salem RM Salvi E Sanna S Shi J Sovio U Thompson JR Turchin MC Vandenput L Verlaan DJ Vitart V White CC Ziegler A Almgren P Balmforth AJ Campbell H Citterio L De Grandi A Dominiczak A Duan J Elliott P Elosua R Eriksson JG Freimer NB Geus EJ Glorioso N Haiqing S Hartikainen AL Havulinna AS Hicks AA Hui J Igl W Illig T Jula A Kajantie E Kilpelaumlinen TO Koiranen M Kolcic I Koskinen S Kovacs P Laitinen J Liu J Lokki ML Marusic A Maschio A Meitinger T Mulas A Pareacute G Parker AN Peden JF Petersmann A Pichler I Pietilaumlinen KH Pouta A Ridderstraringle M Rotter JI Sambrook JG Sanders AR Schmidt CO Sinisalo J Smit JH Stringham HM Bragi Walters G Widen E Wild SH Willemsen G Zagato L Zgaga L Zitting P Alavere H Farrall M McArdle WL Nelis M Peters MJ Ripatti S van Meurs JB Aben KK Ardlie KG Beckmann JS Beilby JP Bergman RN Bergmann S Collins FS Cusi D den Heijer M Eiriksdottir G Gejman PV Hall AS Hamsten A Huikuri HV Iribarren C Kaumlhoumlnen M Kaprio J Kathiresan S Kiemeney L Kocher T Launer LJ Lehtimaumlki T Melander O Mosley TH Jr Musk AW Nieminen MS ODonnell CJ Ohlsson C Oostra B Palmer LJ Raitakari O Ridker PM Rioux JD Rissanen A Rivolta C Schunkert H Shuldiner AR Siscovick DS Stumvoll M Toumlnjes A Tuomilehto J van Ommen GJ Viikari J Heath AC Martin NG Montgomery GW Province MA Kayser M Arnold AM Atwood LD Boerwinkle E Chanock SJ Deloukas P Gieger C Groumlnberg H Hall P Hattersley AT Hengstenberg C Hoffman W Lathrop GM Salomaa V Schreiber S Uda M Waterworth D Wright AF Assimes TL Barroso I Hofman A Mohlke KL Boomsma DI Caulfield MJ Cupples LA Erdmann J Fox CS Gudnason V Gyllensten U Harris TB Hayes RB Jarvelin MR Mooser V Munroe PB Ouwehand WH Penninx BW Pramstaller PP Quertermous T Rudan I Samani NJ Spector TD Voumllzke H Watkins H Wilson JF Groop LC Haritunians T Hu FB Kaplan RC Metspalu A North KE Schlessinger D Wareham NJ Hunter DJ OConnell JR Strachan DP Wichmann HE Borecki IB van Duijn CM Schadt EE Thorsteinsdottir U Peltonen L Uitterlinden AG Visscher PM Chatterjee N Loos RJ Boehnke M McCarthy MI Ingelsson E Lindgren CM Abecasis GR Stefansson K Frayling TM Hirschhorn JN
Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen et alNature 2010 Oct 14467(7317)832-8
RISK SCORE METHOD
PROCAMFramingham Classical Risk factors
0
025
05
075
1
10 105 11 115 12 125 13 135
Risk Score
Pro
ba
bil
ity
no CHD CHD Set Specificity at
5 False Positive
in no-CAD
11 of men who get
CAD have baseline
score over cut-off
89 of the events that occurred over 10 years
would not be predicted by the score
Can we improve on this with genotypes
Whıch genes
to study
20
Genotype - smoking interactions
in risk score
Better than classical +
genotypes plt00001
Adding Environment-Genotype interactions
enhances (DOUBLES) risk prediction score
0
02
04
06
6 7 8 9 10 11 12
Risk score
pro
bab
ilit
y
no CHD CHD
EVEN BETTER
24 of cases
have score
over cut-off
5 FPR
Classical Risk factors + Genotypes + Smokıng
22
2001
Cui Y Wei QQ Park HK amp Lieber CM Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species Science 293 1289ndash1292 (2001)
ldquoDevices based on nanowires are emerging as a powerful platform for the direct detection of biological and chemical species including low concentrations of proteins and virusesrdquo 1st July 2006 Analytic Chemistry
No
rma
lise
d
con
du
ctan
ce c
han
ge
Figure 18 | taken from E Stern JF Klemic DA Routenberg PN Wyrembak DB
Turner-Evans AD Hamilton DA LaVan TM Fahmy and MA Reed Label-free
immunodetection with CMOS-compatible semiconducting nanowires Nature 445
05498 (2007)
Born April 2014
Nanowire chip
DNA extraction
PCR
ldquoHandheldrdquo
Arrived from the engineers at A Star Singapore LAST WEEK
First cassettes Chloroquine resistant Malaria warfarin BRAF
tumour marker
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated
August 2010 China National Highway 110 traffic jam China worldrsquos worst
traffic jam everhellip
more than 100 kilometres from August 14 - 26 inc at least 11 days of total
gridlock
We are heading for the biggest traffic jam in history
Hereditary colorectal cancer Should I request colonoscopy
Donna-Marie Ian
25 24
Positive FH
MSI high tumour
MLH1 leu559arg
Missense
Not inherited
Robert Hofstra
Rolf Sijmons
Westernno expression
Pulldown no interaction
MAPP-MMR and SIFT v2
Suggest pathogenic
Polyphen inconclusive
Reported Belvederesi EJHG
2006
Grantham Variation (GV) and Deviation (GD)
C
P
V Grantham R Science 185 862-864 1974
Tavtigian et al JMG 43 295 2006
GV
GD
HVP4 UNESCO Headquarters Paris 11-15 June 2012
Estimates of Heritability
Disorder Frequency () ()
bull Schizophrenia 1 85
bull Asthma 4 80
bull Ankylosing spondylitis 02 70
bull Neural tube defects 02 60
bull Congenital heart disease 05 60
21
bull Paper by Galton
ldquoChildren regress to
Mediocrityrdquo
Imagine if there were only 2 genes for height each with only 2 alleles H or T of equal
frequency
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
10
We discover one of the genes and call it BYH1 somebody would suggest using it for disease
prediction
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
average short Very
short tall
Very
tall
Always bump
your head
Often bump
Your head
ldquohundreds of variants in at least 180 loci influence human heightrdquo
Nature 2010 Oct 14467(7317)832-8 doi 101038nature09410 Epub 2010 Sep 29 Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen H1 Estrada K Lettre G Berndt SI Weedon MN Rivadeneira F Willer CJ Jackson AU Vedantam S Raychaudhuri S Ferreira T Wood AR Weyant RJ Segregrave AV Speliotes EK Wheeler E Soranzo N Park JH Yang J Gudbjartsson D Heard-Costa NL Randall JC Qi L Vernon Smith A Maumlgi R Pastinen T Liang L Heid IM Luan J Thorleifsson G Winkler TW Goddard ME Sin Lo K Palmer C Workalemahu T Aulchenko YS Johansson A Zillikens MC Feitosa MF Esko T Johnson T Ketkar S Kraft P Mangino M Prokopenko I Absher D Albrecht E Ernst F Glazer NL Hayward C Hottenga JJ Jacobs KB Knowles JW Kutalik Z Monda KL Polasek O Preuss M Rayner NW Robertson NR Steinthorsdottir V Tyrer JP Voight BF Wiklund F Xu J Zhao JH Nyholt DR Pellikka N Perola M Perry JR Surakka I Tammesoo ML Altmaier EL Amin N Aspelund T Bhangale T Boucher G Chasman DI Chen C Coin L Cooper MN Dixon AL Gibson Q Grundberg E Hao K Juhani Junttila M Kaplan LM Kettunen J Koumlnig IR Kwan T Lawrence RW Levinson DF Lorentzon M McKnight B Morris AP Muumlller M Suh Ngwa J Purcell S Rafelt S Salem RM Salvi E Sanna S Shi J Sovio U Thompson JR Turchin MC Vandenput L Verlaan DJ Vitart V White CC Ziegler A Almgren P Balmforth AJ Campbell H Citterio L De Grandi A Dominiczak A Duan J Elliott P Elosua R Eriksson JG Freimer NB Geus EJ Glorioso N Haiqing S Hartikainen AL Havulinna AS Hicks AA Hui J Igl W Illig T Jula A Kajantie E Kilpelaumlinen TO Koiranen M Kolcic I Koskinen S Kovacs P Laitinen J Liu J Lokki ML Marusic A Maschio A Meitinger T Mulas A Pareacute G Parker AN Peden JF Petersmann A Pichler I Pietilaumlinen KH Pouta A Ridderstraringle M Rotter JI Sambrook JG Sanders AR Schmidt CO Sinisalo J Smit JH Stringham HM Bragi Walters G Widen E Wild SH Willemsen G Zagato L Zgaga L Zitting P Alavere H Farrall M McArdle WL Nelis M Peters MJ Ripatti S van Meurs JB Aben KK Ardlie KG Beckmann JS Beilby JP Bergman RN Bergmann S Collins FS Cusi D den Heijer M Eiriksdottir G Gejman PV Hall AS Hamsten A Huikuri HV Iribarren C Kaumlhoumlnen M Kaprio J Kathiresan S Kiemeney L Kocher T Launer LJ Lehtimaumlki T Melander O Mosley TH Jr Musk AW Nieminen MS ODonnell CJ Ohlsson C Oostra B Palmer LJ Raitakari O Ridker PM Rioux JD Rissanen A Rivolta C Schunkert H Shuldiner AR Siscovick DS Stumvoll M Toumlnjes A Tuomilehto J van Ommen GJ Viikari J Heath AC Martin NG Montgomery GW Province MA Kayser M Arnold AM Atwood LD Boerwinkle E Chanock SJ Deloukas P Gieger C Groumlnberg H Hall P Hattersley AT Hengstenberg C Hoffman W Lathrop GM Salomaa V Schreiber S Uda M Waterworth D Wright AF Assimes TL Barroso I Hofman A Mohlke KL Boomsma DI Caulfield MJ Cupples LA Erdmann J Fox CS Gudnason V Gyllensten U Harris TB Hayes RB Jarvelin MR Mooser V Munroe PB Ouwehand WH Penninx BW Pramstaller PP Quertermous T Rudan I Samani NJ Spector TD Voumllzke H Watkins H Wilson JF Groop LC Haritunians T Hu FB Kaplan RC Metspalu A North KE Schlessinger D Wareham NJ Hunter DJ OConnell JR Strachan DP Wichmann HE Borecki IB van Duijn CM Schadt EE Thorsteinsdottir U Peltonen L Uitterlinden AG Visscher PM Chatterjee N Loos RJ Boehnke M McCarthy MI Ingelsson E Lindgren CM Abecasis GR Stefansson K Frayling TM Hirschhorn JN
Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen et alNature 2010 Oct 14467(7317)832-8
RISK SCORE METHOD
PROCAMFramingham Classical Risk factors
0
025
05
075
1
10 105 11 115 12 125 13 135
Risk Score
Pro
ba
bil
ity
no CHD CHD Set Specificity at
5 False Positive
in no-CAD
11 of men who get
CAD have baseline
score over cut-off
89 of the events that occurred over 10 years
would not be predicted by the score
Can we improve on this with genotypes
Whıch genes
to study
20
Genotype - smoking interactions
in risk score
Better than classical +
genotypes plt00001
Adding Environment-Genotype interactions
enhances (DOUBLES) risk prediction score
0
02
04
06
6 7 8 9 10 11 12
Risk score
pro
bab
ilit
y
no CHD CHD
EVEN BETTER
24 of cases
have score
over cut-off
5 FPR
Classical Risk factors + Genotypes + Smokıng
22
2001
Cui Y Wei QQ Park HK amp Lieber CM Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species Science 293 1289ndash1292 (2001)
ldquoDevices based on nanowires are emerging as a powerful platform for the direct detection of biological and chemical species including low concentrations of proteins and virusesrdquo 1st July 2006 Analytic Chemistry
No
rma
lise
d
con
du
ctan
ce c
han
ge
Figure 18 | taken from E Stern JF Klemic DA Routenberg PN Wyrembak DB
Turner-Evans AD Hamilton DA LaVan TM Fahmy and MA Reed Label-free
immunodetection with CMOS-compatible semiconducting nanowires Nature 445
05498 (2007)
Born April 2014
Nanowire chip
DNA extraction
PCR
ldquoHandheldrdquo
Arrived from the engineers at A Star Singapore LAST WEEK
First cassettes Chloroquine resistant Malaria warfarin BRAF
tumour marker
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated
Hereditary colorectal cancer Should I request colonoscopy
Donna-Marie Ian
25 24
Positive FH
MSI high tumour
MLH1 leu559arg
Missense
Not inherited
Robert Hofstra
Rolf Sijmons
Westernno expression
Pulldown no interaction
MAPP-MMR and SIFT v2
Suggest pathogenic
Polyphen inconclusive
Reported Belvederesi EJHG
2006
Grantham Variation (GV) and Deviation (GD)
C
P
V Grantham R Science 185 862-864 1974
Tavtigian et al JMG 43 295 2006
GV
GD
HVP4 UNESCO Headquarters Paris 11-15 June 2012
Estimates of Heritability
Disorder Frequency () ()
bull Schizophrenia 1 85
bull Asthma 4 80
bull Ankylosing spondylitis 02 70
bull Neural tube defects 02 60
bull Congenital heart disease 05 60
21
bull Paper by Galton
ldquoChildren regress to
Mediocrityrdquo
Imagine if there were only 2 genes for height each with only 2 alleles H or T of equal
frequency
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
10
We discover one of the genes and call it BYH1 somebody would suggest using it for disease
prediction
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
average short Very
short tall
Very
tall
Always bump
your head
Often bump
Your head
ldquohundreds of variants in at least 180 loci influence human heightrdquo
Nature 2010 Oct 14467(7317)832-8 doi 101038nature09410 Epub 2010 Sep 29 Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen H1 Estrada K Lettre G Berndt SI Weedon MN Rivadeneira F Willer CJ Jackson AU Vedantam S Raychaudhuri S Ferreira T Wood AR Weyant RJ Segregrave AV Speliotes EK Wheeler E Soranzo N Park JH Yang J Gudbjartsson D Heard-Costa NL Randall JC Qi L Vernon Smith A Maumlgi R Pastinen T Liang L Heid IM Luan J Thorleifsson G Winkler TW Goddard ME Sin Lo K Palmer C Workalemahu T Aulchenko YS Johansson A Zillikens MC Feitosa MF Esko T Johnson T Ketkar S Kraft P Mangino M Prokopenko I Absher D Albrecht E Ernst F Glazer NL Hayward C Hottenga JJ Jacobs KB Knowles JW Kutalik Z Monda KL Polasek O Preuss M Rayner NW Robertson NR Steinthorsdottir V Tyrer JP Voight BF Wiklund F Xu J Zhao JH Nyholt DR Pellikka N Perola M Perry JR Surakka I Tammesoo ML Altmaier EL Amin N Aspelund T Bhangale T Boucher G Chasman DI Chen C Coin L Cooper MN Dixon AL Gibson Q Grundberg E Hao K Juhani Junttila M Kaplan LM Kettunen J Koumlnig IR Kwan T Lawrence RW Levinson DF Lorentzon M McKnight B Morris AP Muumlller M Suh Ngwa J Purcell S Rafelt S Salem RM Salvi E Sanna S Shi J Sovio U Thompson JR Turchin MC Vandenput L Verlaan DJ Vitart V White CC Ziegler A Almgren P Balmforth AJ Campbell H Citterio L De Grandi A Dominiczak A Duan J Elliott P Elosua R Eriksson JG Freimer NB Geus EJ Glorioso N Haiqing S Hartikainen AL Havulinna AS Hicks AA Hui J Igl W Illig T Jula A Kajantie E Kilpelaumlinen TO Koiranen M Kolcic I Koskinen S Kovacs P Laitinen J Liu J Lokki ML Marusic A Maschio A Meitinger T Mulas A Pareacute G Parker AN Peden JF Petersmann A Pichler I Pietilaumlinen KH Pouta A Ridderstraringle M Rotter JI Sambrook JG Sanders AR Schmidt CO Sinisalo J Smit JH Stringham HM Bragi Walters G Widen E Wild SH Willemsen G Zagato L Zgaga L Zitting P Alavere H Farrall M McArdle WL Nelis M Peters MJ Ripatti S van Meurs JB Aben KK Ardlie KG Beckmann JS Beilby JP Bergman RN Bergmann S Collins FS Cusi D den Heijer M Eiriksdottir G Gejman PV Hall AS Hamsten A Huikuri HV Iribarren C Kaumlhoumlnen M Kaprio J Kathiresan S Kiemeney L Kocher T Launer LJ Lehtimaumlki T Melander O Mosley TH Jr Musk AW Nieminen MS ODonnell CJ Ohlsson C Oostra B Palmer LJ Raitakari O Ridker PM Rioux JD Rissanen A Rivolta C Schunkert H Shuldiner AR Siscovick DS Stumvoll M Toumlnjes A Tuomilehto J van Ommen GJ Viikari J Heath AC Martin NG Montgomery GW Province MA Kayser M Arnold AM Atwood LD Boerwinkle E Chanock SJ Deloukas P Gieger C Groumlnberg H Hall P Hattersley AT Hengstenberg C Hoffman W Lathrop GM Salomaa V Schreiber S Uda M Waterworth D Wright AF Assimes TL Barroso I Hofman A Mohlke KL Boomsma DI Caulfield MJ Cupples LA Erdmann J Fox CS Gudnason V Gyllensten U Harris TB Hayes RB Jarvelin MR Mooser V Munroe PB Ouwehand WH Penninx BW Pramstaller PP Quertermous T Rudan I Samani NJ Spector TD Voumllzke H Watkins H Wilson JF Groop LC Haritunians T Hu FB Kaplan RC Metspalu A North KE Schlessinger D Wareham NJ Hunter DJ OConnell JR Strachan DP Wichmann HE Borecki IB van Duijn CM Schadt EE Thorsteinsdottir U Peltonen L Uitterlinden AG Visscher PM Chatterjee N Loos RJ Boehnke M McCarthy MI Ingelsson E Lindgren CM Abecasis GR Stefansson K Frayling TM Hirschhorn JN
Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen et alNature 2010 Oct 14467(7317)832-8
RISK SCORE METHOD
PROCAMFramingham Classical Risk factors
0
025
05
075
1
10 105 11 115 12 125 13 135
Risk Score
Pro
ba
bil
ity
no CHD CHD Set Specificity at
5 False Positive
in no-CAD
11 of men who get
CAD have baseline
score over cut-off
89 of the events that occurred over 10 years
would not be predicted by the score
Can we improve on this with genotypes
Whıch genes
to study
20
Genotype - smoking interactions
in risk score
Better than classical +
genotypes plt00001
Adding Environment-Genotype interactions
enhances (DOUBLES) risk prediction score
0
02
04
06
6 7 8 9 10 11 12
Risk score
pro
bab
ilit
y
no CHD CHD
EVEN BETTER
24 of cases
have score
over cut-off
5 FPR
Classical Risk factors + Genotypes + Smokıng
22
2001
Cui Y Wei QQ Park HK amp Lieber CM Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species Science 293 1289ndash1292 (2001)
ldquoDevices based on nanowires are emerging as a powerful platform for the direct detection of biological and chemical species including low concentrations of proteins and virusesrdquo 1st July 2006 Analytic Chemistry
No
rma
lise
d
con
du
ctan
ce c
han
ge
Figure 18 | taken from E Stern JF Klemic DA Routenberg PN Wyrembak DB
Turner-Evans AD Hamilton DA LaVan TM Fahmy and MA Reed Label-free
immunodetection with CMOS-compatible semiconducting nanowires Nature 445
05498 (2007)
Born April 2014
Nanowire chip
DNA extraction
PCR
ldquoHandheldrdquo
Arrived from the engineers at A Star Singapore LAST WEEK
First cassettes Chloroquine resistant Malaria warfarin BRAF
tumour marker
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated
Grantham Variation (GV) and Deviation (GD)
C
P
V Grantham R Science 185 862-864 1974
Tavtigian et al JMG 43 295 2006
GV
GD
HVP4 UNESCO Headquarters Paris 11-15 June 2012
Estimates of Heritability
Disorder Frequency () ()
bull Schizophrenia 1 85
bull Asthma 4 80
bull Ankylosing spondylitis 02 70
bull Neural tube defects 02 60
bull Congenital heart disease 05 60
21
bull Paper by Galton
ldquoChildren regress to
Mediocrityrdquo
Imagine if there were only 2 genes for height each with only 2 alleles H or T of equal
frequency
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
10
We discover one of the genes and call it BYH1 somebody would suggest using it for disease
prediction
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
average short Very
short tall
Very
tall
Always bump
your head
Often bump
Your head
ldquohundreds of variants in at least 180 loci influence human heightrdquo
Nature 2010 Oct 14467(7317)832-8 doi 101038nature09410 Epub 2010 Sep 29 Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen H1 Estrada K Lettre G Berndt SI Weedon MN Rivadeneira F Willer CJ Jackson AU Vedantam S Raychaudhuri S Ferreira T Wood AR Weyant RJ Segregrave AV Speliotes EK Wheeler E Soranzo N Park JH Yang J Gudbjartsson D Heard-Costa NL Randall JC Qi L Vernon Smith A Maumlgi R Pastinen T Liang L Heid IM Luan J Thorleifsson G Winkler TW Goddard ME Sin Lo K Palmer C Workalemahu T Aulchenko YS Johansson A Zillikens MC Feitosa MF Esko T Johnson T Ketkar S Kraft P Mangino M Prokopenko I Absher D Albrecht E Ernst F Glazer NL Hayward C Hottenga JJ Jacobs KB Knowles JW Kutalik Z Monda KL Polasek O Preuss M Rayner NW Robertson NR Steinthorsdottir V Tyrer JP Voight BF Wiklund F Xu J Zhao JH Nyholt DR Pellikka N Perola M Perry JR Surakka I Tammesoo ML Altmaier EL Amin N Aspelund T Bhangale T Boucher G Chasman DI Chen C Coin L Cooper MN Dixon AL Gibson Q Grundberg E Hao K Juhani Junttila M Kaplan LM Kettunen J Koumlnig IR Kwan T Lawrence RW Levinson DF Lorentzon M McKnight B Morris AP Muumlller M Suh Ngwa J Purcell S Rafelt S Salem RM Salvi E Sanna S Shi J Sovio U Thompson JR Turchin MC Vandenput L Verlaan DJ Vitart V White CC Ziegler A Almgren P Balmforth AJ Campbell H Citterio L De Grandi A Dominiczak A Duan J Elliott P Elosua R Eriksson JG Freimer NB Geus EJ Glorioso N Haiqing S Hartikainen AL Havulinna AS Hicks AA Hui J Igl W Illig T Jula A Kajantie E Kilpelaumlinen TO Koiranen M Kolcic I Koskinen S Kovacs P Laitinen J Liu J Lokki ML Marusic A Maschio A Meitinger T Mulas A Pareacute G Parker AN Peden JF Petersmann A Pichler I Pietilaumlinen KH Pouta A Ridderstraringle M Rotter JI Sambrook JG Sanders AR Schmidt CO Sinisalo J Smit JH Stringham HM Bragi Walters G Widen E Wild SH Willemsen G Zagato L Zgaga L Zitting P Alavere H Farrall M McArdle WL Nelis M Peters MJ Ripatti S van Meurs JB Aben KK Ardlie KG Beckmann JS Beilby JP Bergman RN Bergmann S Collins FS Cusi D den Heijer M Eiriksdottir G Gejman PV Hall AS Hamsten A Huikuri HV Iribarren C Kaumlhoumlnen M Kaprio J Kathiresan S Kiemeney L Kocher T Launer LJ Lehtimaumlki T Melander O Mosley TH Jr Musk AW Nieminen MS ODonnell CJ Ohlsson C Oostra B Palmer LJ Raitakari O Ridker PM Rioux JD Rissanen A Rivolta C Schunkert H Shuldiner AR Siscovick DS Stumvoll M Toumlnjes A Tuomilehto J van Ommen GJ Viikari J Heath AC Martin NG Montgomery GW Province MA Kayser M Arnold AM Atwood LD Boerwinkle E Chanock SJ Deloukas P Gieger C Groumlnberg H Hall P Hattersley AT Hengstenberg C Hoffman W Lathrop GM Salomaa V Schreiber S Uda M Waterworth D Wright AF Assimes TL Barroso I Hofman A Mohlke KL Boomsma DI Caulfield MJ Cupples LA Erdmann J Fox CS Gudnason V Gyllensten U Harris TB Hayes RB Jarvelin MR Mooser V Munroe PB Ouwehand WH Penninx BW Pramstaller PP Quertermous T Rudan I Samani NJ Spector TD Voumllzke H Watkins H Wilson JF Groop LC Haritunians T Hu FB Kaplan RC Metspalu A North KE Schlessinger D Wareham NJ Hunter DJ OConnell JR Strachan DP Wichmann HE Borecki IB van Duijn CM Schadt EE Thorsteinsdottir U Peltonen L Uitterlinden AG Visscher PM Chatterjee N Loos RJ Boehnke M McCarthy MI Ingelsson E Lindgren CM Abecasis GR Stefansson K Frayling TM Hirschhorn JN
Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen et alNature 2010 Oct 14467(7317)832-8
RISK SCORE METHOD
PROCAMFramingham Classical Risk factors
0
025
05
075
1
10 105 11 115 12 125 13 135
Risk Score
Pro
ba
bil
ity
no CHD CHD Set Specificity at
5 False Positive
in no-CAD
11 of men who get
CAD have baseline
score over cut-off
89 of the events that occurred over 10 years
would not be predicted by the score
Can we improve on this with genotypes
Whıch genes
to study
20
Genotype - smoking interactions
in risk score
Better than classical +
genotypes plt00001
Adding Environment-Genotype interactions
enhances (DOUBLES) risk prediction score
0
02
04
06
6 7 8 9 10 11 12
Risk score
pro
bab
ilit
y
no CHD CHD
EVEN BETTER
24 of cases
have score
over cut-off
5 FPR
Classical Risk factors + Genotypes + Smokıng
22
2001
Cui Y Wei QQ Park HK amp Lieber CM Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species Science 293 1289ndash1292 (2001)
ldquoDevices based on nanowires are emerging as a powerful platform for the direct detection of biological and chemical species including low concentrations of proteins and virusesrdquo 1st July 2006 Analytic Chemistry
No
rma
lise
d
con
du
ctan
ce c
han
ge
Figure 18 | taken from E Stern JF Klemic DA Routenberg PN Wyrembak DB
Turner-Evans AD Hamilton DA LaVan TM Fahmy and MA Reed Label-free
immunodetection with CMOS-compatible semiconducting nanowires Nature 445
05498 (2007)
Born April 2014
Nanowire chip
DNA extraction
PCR
ldquoHandheldrdquo
Arrived from the engineers at A Star Singapore LAST WEEK
First cassettes Chloroquine resistant Malaria warfarin BRAF
tumour marker
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated
HVP4 UNESCO Headquarters Paris 11-15 June 2012
Estimates of Heritability
Disorder Frequency () ()
bull Schizophrenia 1 85
bull Asthma 4 80
bull Ankylosing spondylitis 02 70
bull Neural tube defects 02 60
bull Congenital heart disease 05 60
21
bull Paper by Galton
ldquoChildren regress to
Mediocrityrdquo
Imagine if there were only 2 genes for height each with only 2 alleles H or T of equal
frequency
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
10
We discover one of the genes and call it BYH1 somebody would suggest using it for disease
prediction
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
average short Very
short tall
Very
tall
Always bump
your head
Often bump
Your head
ldquohundreds of variants in at least 180 loci influence human heightrdquo
Nature 2010 Oct 14467(7317)832-8 doi 101038nature09410 Epub 2010 Sep 29 Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen H1 Estrada K Lettre G Berndt SI Weedon MN Rivadeneira F Willer CJ Jackson AU Vedantam S Raychaudhuri S Ferreira T Wood AR Weyant RJ Segregrave AV Speliotes EK Wheeler E Soranzo N Park JH Yang J Gudbjartsson D Heard-Costa NL Randall JC Qi L Vernon Smith A Maumlgi R Pastinen T Liang L Heid IM Luan J Thorleifsson G Winkler TW Goddard ME Sin Lo K Palmer C Workalemahu T Aulchenko YS Johansson A Zillikens MC Feitosa MF Esko T Johnson T Ketkar S Kraft P Mangino M Prokopenko I Absher D Albrecht E Ernst F Glazer NL Hayward C Hottenga JJ Jacobs KB Knowles JW Kutalik Z Monda KL Polasek O Preuss M Rayner NW Robertson NR Steinthorsdottir V Tyrer JP Voight BF Wiklund F Xu J Zhao JH Nyholt DR Pellikka N Perola M Perry JR Surakka I Tammesoo ML Altmaier EL Amin N Aspelund T Bhangale T Boucher G Chasman DI Chen C Coin L Cooper MN Dixon AL Gibson Q Grundberg E Hao K Juhani Junttila M Kaplan LM Kettunen J Koumlnig IR Kwan T Lawrence RW Levinson DF Lorentzon M McKnight B Morris AP Muumlller M Suh Ngwa J Purcell S Rafelt S Salem RM Salvi E Sanna S Shi J Sovio U Thompson JR Turchin MC Vandenput L Verlaan DJ Vitart V White CC Ziegler A Almgren P Balmforth AJ Campbell H Citterio L De Grandi A Dominiczak A Duan J Elliott P Elosua R Eriksson JG Freimer NB Geus EJ Glorioso N Haiqing S Hartikainen AL Havulinna AS Hicks AA Hui J Igl W Illig T Jula A Kajantie E Kilpelaumlinen TO Koiranen M Kolcic I Koskinen S Kovacs P Laitinen J Liu J Lokki ML Marusic A Maschio A Meitinger T Mulas A Pareacute G Parker AN Peden JF Petersmann A Pichler I Pietilaumlinen KH Pouta A Ridderstraringle M Rotter JI Sambrook JG Sanders AR Schmidt CO Sinisalo J Smit JH Stringham HM Bragi Walters G Widen E Wild SH Willemsen G Zagato L Zgaga L Zitting P Alavere H Farrall M McArdle WL Nelis M Peters MJ Ripatti S van Meurs JB Aben KK Ardlie KG Beckmann JS Beilby JP Bergman RN Bergmann S Collins FS Cusi D den Heijer M Eiriksdottir G Gejman PV Hall AS Hamsten A Huikuri HV Iribarren C Kaumlhoumlnen M Kaprio J Kathiresan S Kiemeney L Kocher T Launer LJ Lehtimaumlki T Melander O Mosley TH Jr Musk AW Nieminen MS ODonnell CJ Ohlsson C Oostra B Palmer LJ Raitakari O Ridker PM Rioux JD Rissanen A Rivolta C Schunkert H Shuldiner AR Siscovick DS Stumvoll M Toumlnjes A Tuomilehto J van Ommen GJ Viikari J Heath AC Martin NG Montgomery GW Province MA Kayser M Arnold AM Atwood LD Boerwinkle E Chanock SJ Deloukas P Gieger C Groumlnberg H Hall P Hattersley AT Hengstenberg C Hoffman W Lathrop GM Salomaa V Schreiber S Uda M Waterworth D Wright AF Assimes TL Barroso I Hofman A Mohlke KL Boomsma DI Caulfield MJ Cupples LA Erdmann J Fox CS Gudnason V Gyllensten U Harris TB Hayes RB Jarvelin MR Mooser V Munroe PB Ouwehand WH Penninx BW Pramstaller PP Quertermous T Rudan I Samani NJ Spector TD Voumllzke H Watkins H Wilson JF Groop LC Haritunians T Hu FB Kaplan RC Metspalu A North KE Schlessinger D Wareham NJ Hunter DJ OConnell JR Strachan DP Wichmann HE Borecki IB van Duijn CM Schadt EE Thorsteinsdottir U Peltonen L Uitterlinden AG Visscher PM Chatterjee N Loos RJ Boehnke M McCarthy MI Ingelsson E Lindgren CM Abecasis GR Stefansson K Frayling TM Hirschhorn JN
Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen et alNature 2010 Oct 14467(7317)832-8
RISK SCORE METHOD
PROCAMFramingham Classical Risk factors
0
025
05
075
1
10 105 11 115 12 125 13 135
Risk Score
Pro
ba
bil
ity
no CHD CHD Set Specificity at
5 False Positive
in no-CAD
11 of men who get
CAD have baseline
score over cut-off
89 of the events that occurred over 10 years
would not be predicted by the score
Can we improve on this with genotypes
Whıch genes
to study
20
Genotype - smoking interactions
in risk score
Better than classical +
genotypes plt00001
Adding Environment-Genotype interactions
enhances (DOUBLES) risk prediction score
0
02
04
06
6 7 8 9 10 11 12
Risk score
pro
bab
ilit
y
no CHD CHD
EVEN BETTER
24 of cases
have score
over cut-off
5 FPR
Classical Risk factors + Genotypes + Smokıng
22
2001
Cui Y Wei QQ Park HK amp Lieber CM Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species Science 293 1289ndash1292 (2001)
ldquoDevices based on nanowires are emerging as a powerful platform for the direct detection of biological and chemical species including low concentrations of proteins and virusesrdquo 1st July 2006 Analytic Chemistry
No
rma
lise
d
con
du
ctan
ce c
han
ge
Figure 18 | taken from E Stern JF Klemic DA Routenberg PN Wyrembak DB
Turner-Evans AD Hamilton DA LaVan TM Fahmy and MA Reed Label-free
immunodetection with CMOS-compatible semiconducting nanowires Nature 445
05498 (2007)
Born April 2014
Nanowire chip
DNA extraction
PCR
ldquoHandheldrdquo
Arrived from the engineers at A Star Singapore LAST WEEK
First cassettes Chloroquine resistant Malaria warfarin BRAF
tumour marker
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated
Estimates of Heritability
Disorder Frequency () ()
bull Schizophrenia 1 85
bull Asthma 4 80
bull Ankylosing spondylitis 02 70
bull Neural tube defects 02 60
bull Congenital heart disease 05 60
21
bull Paper by Galton
ldquoChildren regress to
Mediocrityrdquo
Imagine if there were only 2 genes for height each with only 2 alleles H or T of equal
frequency
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
10
We discover one of the genes and call it BYH1 somebody would suggest using it for disease
prediction
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
average short Very
short tall
Very
tall
Always bump
your head
Often bump
Your head
ldquohundreds of variants in at least 180 loci influence human heightrdquo
Nature 2010 Oct 14467(7317)832-8 doi 101038nature09410 Epub 2010 Sep 29 Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen H1 Estrada K Lettre G Berndt SI Weedon MN Rivadeneira F Willer CJ Jackson AU Vedantam S Raychaudhuri S Ferreira T Wood AR Weyant RJ Segregrave AV Speliotes EK Wheeler E Soranzo N Park JH Yang J Gudbjartsson D Heard-Costa NL Randall JC Qi L Vernon Smith A Maumlgi R Pastinen T Liang L Heid IM Luan J Thorleifsson G Winkler TW Goddard ME Sin Lo K Palmer C Workalemahu T Aulchenko YS Johansson A Zillikens MC Feitosa MF Esko T Johnson T Ketkar S Kraft P Mangino M Prokopenko I Absher D Albrecht E Ernst F Glazer NL Hayward C Hottenga JJ Jacobs KB Knowles JW Kutalik Z Monda KL Polasek O Preuss M Rayner NW Robertson NR Steinthorsdottir V Tyrer JP Voight BF Wiklund F Xu J Zhao JH Nyholt DR Pellikka N Perola M Perry JR Surakka I Tammesoo ML Altmaier EL Amin N Aspelund T Bhangale T Boucher G Chasman DI Chen C Coin L Cooper MN Dixon AL Gibson Q Grundberg E Hao K Juhani Junttila M Kaplan LM Kettunen J Koumlnig IR Kwan T Lawrence RW Levinson DF Lorentzon M McKnight B Morris AP Muumlller M Suh Ngwa J Purcell S Rafelt S Salem RM Salvi E Sanna S Shi J Sovio U Thompson JR Turchin MC Vandenput L Verlaan DJ Vitart V White CC Ziegler A Almgren P Balmforth AJ Campbell H Citterio L De Grandi A Dominiczak A Duan J Elliott P Elosua R Eriksson JG Freimer NB Geus EJ Glorioso N Haiqing S Hartikainen AL Havulinna AS Hicks AA Hui J Igl W Illig T Jula A Kajantie E Kilpelaumlinen TO Koiranen M Kolcic I Koskinen S Kovacs P Laitinen J Liu J Lokki ML Marusic A Maschio A Meitinger T Mulas A Pareacute G Parker AN Peden JF Petersmann A Pichler I Pietilaumlinen KH Pouta A Ridderstraringle M Rotter JI Sambrook JG Sanders AR Schmidt CO Sinisalo J Smit JH Stringham HM Bragi Walters G Widen E Wild SH Willemsen G Zagato L Zgaga L Zitting P Alavere H Farrall M McArdle WL Nelis M Peters MJ Ripatti S van Meurs JB Aben KK Ardlie KG Beckmann JS Beilby JP Bergman RN Bergmann S Collins FS Cusi D den Heijer M Eiriksdottir G Gejman PV Hall AS Hamsten A Huikuri HV Iribarren C Kaumlhoumlnen M Kaprio J Kathiresan S Kiemeney L Kocher T Launer LJ Lehtimaumlki T Melander O Mosley TH Jr Musk AW Nieminen MS ODonnell CJ Ohlsson C Oostra B Palmer LJ Raitakari O Ridker PM Rioux JD Rissanen A Rivolta C Schunkert H Shuldiner AR Siscovick DS Stumvoll M Toumlnjes A Tuomilehto J van Ommen GJ Viikari J Heath AC Martin NG Montgomery GW Province MA Kayser M Arnold AM Atwood LD Boerwinkle E Chanock SJ Deloukas P Gieger C Groumlnberg H Hall P Hattersley AT Hengstenberg C Hoffman W Lathrop GM Salomaa V Schreiber S Uda M Waterworth D Wright AF Assimes TL Barroso I Hofman A Mohlke KL Boomsma DI Caulfield MJ Cupples LA Erdmann J Fox CS Gudnason V Gyllensten U Harris TB Hayes RB Jarvelin MR Mooser V Munroe PB Ouwehand WH Penninx BW Pramstaller PP Quertermous T Rudan I Samani NJ Spector TD Voumllzke H Watkins H Wilson JF Groop LC Haritunians T Hu FB Kaplan RC Metspalu A North KE Schlessinger D Wareham NJ Hunter DJ OConnell JR Strachan DP Wichmann HE Borecki IB van Duijn CM Schadt EE Thorsteinsdottir U Peltonen L Uitterlinden AG Visscher PM Chatterjee N Loos RJ Boehnke M McCarthy MI Ingelsson E Lindgren CM Abecasis GR Stefansson K Frayling TM Hirschhorn JN
Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen et alNature 2010 Oct 14467(7317)832-8
RISK SCORE METHOD
PROCAMFramingham Classical Risk factors
0
025
05
075
1
10 105 11 115 12 125 13 135
Risk Score
Pro
ba
bil
ity
no CHD CHD Set Specificity at
5 False Positive
in no-CAD
11 of men who get
CAD have baseline
score over cut-off
89 of the events that occurred over 10 years
would not be predicted by the score
Can we improve on this with genotypes
Whıch genes
to study
20
Genotype - smoking interactions
in risk score
Better than classical +
genotypes plt00001
Adding Environment-Genotype interactions
enhances (DOUBLES) risk prediction score
0
02
04
06
6 7 8 9 10 11 12
Risk score
pro
bab
ilit
y
no CHD CHD
EVEN BETTER
24 of cases
have score
over cut-off
5 FPR
Classical Risk factors + Genotypes + Smokıng
22
2001
Cui Y Wei QQ Park HK amp Lieber CM Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species Science 293 1289ndash1292 (2001)
ldquoDevices based on nanowires are emerging as a powerful platform for the direct detection of biological and chemical species including low concentrations of proteins and virusesrdquo 1st July 2006 Analytic Chemistry
No
rma
lise
d
con
du
ctan
ce c
han
ge
Figure 18 | taken from E Stern JF Klemic DA Routenberg PN Wyrembak DB
Turner-Evans AD Hamilton DA LaVan TM Fahmy and MA Reed Label-free
immunodetection with CMOS-compatible semiconducting nanowires Nature 445
05498 (2007)
Born April 2014
Nanowire chip
DNA extraction
PCR
ldquoHandheldrdquo
Arrived from the engineers at A Star Singapore LAST WEEK
First cassettes Chloroquine resistant Malaria warfarin BRAF
tumour marker
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated
bull Paper by Galton
ldquoChildren regress to
Mediocrityrdquo
Imagine if there were only 2 genes for height each with only 2 alleles H or T of equal
frequency
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
10
We discover one of the genes and call it BYH1 somebody would suggest using it for disease
prediction
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
average short Very
short tall
Very
tall
Always bump
your head
Often bump
Your head
ldquohundreds of variants in at least 180 loci influence human heightrdquo
Nature 2010 Oct 14467(7317)832-8 doi 101038nature09410 Epub 2010 Sep 29 Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen H1 Estrada K Lettre G Berndt SI Weedon MN Rivadeneira F Willer CJ Jackson AU Vedantam S Raychaudhuri S Ferreira T Wood AR Weyant RJ Segregrave AV Speliotes EK Wheeler E Soranzo N Park JH Yang J Gudbjartsson D Heard-Costa NL Randall JC Qi L Vernon Smith A Maumlgi R Pastinen T Liang L Heid IM Luan J Thorleifsson G Winkler TW Goddard ME Sin Lo K Palmer C Workalemahu T Aulchenko YS Johansson A Zillikens MC Feitosa MF Esko T Johnson T Ketkar S Kraft P Mangino M Prokopenko I Absher D Albrecht E Ernst F Glazer NL Hayward C Hottenga JJ Jacobs KB Knowles JW Kutalik Z Monda KL Polasek O Preuss M Rayner NW Robertson NR Steinthorsdottir V Tyrer JP Voight BF Wiklund F Xu J Zhao JH Nyholt DR Pellikka N Perola M Perry JR Surakka I Tammesoo ML Altmaier EL Amin N Aspelund T Bhangale T Boucher G Chasman DI Chen C Coin L Cooper MN Dixon AL Gibson Q Grundberg E Hao K Juhani Junttila M Kaplan LM Kettunen J Koumlnig IR Kwan T Lawrence RW Levinson DF Lorentzon M McKnight B Morris AP Muumlller M Suh Ngwa J Purcell S Rafelt S Salem RM Salvi E Sanna S Shi J Sovio U Thompson JR Turchin MC Vandenput L Verlaan DJ Vitart V White CC Ziegler A Almgren P Balmforth AJ Campbell H Citterio L De Grandi A Dominiczak A Duan J Elliott P Elosua R Eriksson JG Freimer NB Geus EJ Glorioso N Haiqing S Hartikainen AL Havulinna AS Hicks AA Hui J Igl W Illig T Jula A Kajantie E Kilpelaumlinen TO Koiranen M Kolcic I Koskinen S Kovacs P Laitinen J Liu J Lokki ML Marusic A Maschio A Meitinger T Mulas A Pareacute G Parker AN Peden JF Petersmann A Pichler I Pietilaumlinen KH Pouta A Ridderstraringle M Rotter JI Sambrook JG Sanders AR Schmidt CO Sinisalo J Smit JH Stringham HM Bragi Walters G Widen E Wild SH Willemsen G Zagato L Zgaga L Zitting P Alavere H Farrall M McArdle WL Nelis M Peters MJ Ripatti S van Meurs JB Aben KK Ardlie KG Beckmann JS Beilby JP Bergman RN Bergmann S Collins FS Cusi D den Heijer M Eiriksdottir G Gejman PV Hall AS Hamsten A Huikuri HV Iribarren C Kaumlhoumlnen M Kaprio J Kathiresan S Kiemeney L Kocher T Launer LJ Lehtimaumlki T Melander O Mosley TH Jr Musk AW Nieminen MS ODonnell CJ Ohlsson C Oostra B Palmer LJ Raitakari O Ridker PM Rioux JD Rissanen A Rivolta C Schunkert H Shuldiner AR Siscovick DS Stumvoll M Toumlnjes A Tuomilehto J van Ommen GJ Viikari J Heath AC Martin NG Montgomery GW Province MA Kayser M Arnold AM Atwood LD Boerwinkle E Chanock SJ Deloukas P Gieger C Groumlnberg H Hall P Hattersley AT Hengstenberg C Hoffman W Lathrop GM Salomaa V Schreiber S Uda M Waterworth D Wright AF Assimes TL Barroso I Hofman A Mohlke KL Boomsma DI Caulfield MJ Cupples LA Erdmann J Fox CS Gudnason V Gyllensten U Harris TB Hayes RB Jarvelin MR Mooser V Munroe PB Ouwehand WH Penninx BW Pramstaller PP Quertermous T Rudan I Samani NJ Spector TD Voumllzke H Watkins H Wilson JF Groop LC Haritunians T Hu FB Kaplan RC Metspalu A North KE Schlessinger D Wareham NJ Hunter DJ OConnell JR Strachan DP Wichmann HE Borecki IB van Duijn CM Schadt EE Thorsteinsdottir U Peltonen L Uitterlinden AG Visscher PM Chatterjee N Loos RJ Boehnke M McCarthy MI Ingelsson E Lindgren CM Abecasis GR Stefansson K Frayling TM Hirschhorn JN
Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen et alNature 2010 Oct 14467(7317)832-8
RISK SCORE METHOD
PROCAMFramingham Classical Risk factors
0
025
05
075
1
10 105 11 115 12 125 13 135
Risk Score
Pro
ba
bil
ity
no CHD CHD Set Specificity at
5 False Positive
in no-CAD
11 of men who get
CAD have baseline
score over cut-off
89 of the events that occurred over 10 years
would not be predicted by the score
Can we improve on this with genotypes
Whıch genes
to study
20
Genotype - smoking interactions
in risk score
Better than classical +
genotypes plt00001
Adding Environment-Genotype interactions
enhances (DOUBLES) risk prediction score
0
02
04
06
6 7 8 9 10 11 12
Risk score
pro
bab
ilit
y
no CHD CHD
EVEN BETTER
24 of cases
have score
over cut-off
5 FPR
Classical Risk factors + Genotypes + Smokıng
22
2001
Cui Y Wei QQ Park HK amp Lieber CM Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species Science 293 1289ndash1292 (2001)
ldquoDevices based on nanowires are emerging as a powerful platform for the direct detection of biological and chemical species including low concentrations of proteins and virusesrdquo 1st July 2006 Analytic Chemistry
No
rma
lise
d
con
du
ctan
ce c
han
ge
Figure 18 | taken from E Stern JF Klemic DA Routenberg PN Wyrembak DB
Turner-Evans AD Hamilton DA LaVan TM Fahmy and MA Reed Label-free
immunodetection with CMOS-compatible semiconducting nanowires Nature 445
05498 (2007)
Born April 2014
Nanowire chip
DNA extraction
PCR
ldquoHandheldrdquo
Arrived from the engineers at A Star Singapore LAST WEEK
First cassettes Chloroquine resistant Malaria warfarin BRAF
tumour marker
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated
Imagine if there were only 2 genes for height each with only 2 alleles H or T of equal
frequency
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
10
We discover one of the genes and call it BYH1 somebody would suggest using it for disease
prediction
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
average short Very
short tall
Very
tall
Always bump
your head
Often bump
Your head
ldquohundreds of variants in at least 180 loci influence human heightrdquo
Nature 2010 Oct 14467(7317)832-8 doi 101038nature09410 Epub 2010 Sep 29 Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen H1 Estrada K Lettre G Berndt SI Weedon MN Rivadeneira F Willer CJ Jackson AU Vedantam S Raychaudhuri S Ferreira T Wood AR Weyant RJ Segregrave AV Speliotes EK Wheeler E Soranzo N Park JH Yang J Gudbjartsson D Heard-Costa NL Randall JC Qi L Vernon Smith A Maumlgi R Pastinen T Liang L Heid IM Luan J Thorleifsson G Winkler TW Goddard ME Sin Lo K Palmer C Workalemahu T Aulchenko YS Johansson A Zillikens MC Feitosa MF Esko T Johnson T Ketkar S Kraft P Mangino M Prokopenko I Absher D Albrecht E Ernst F Glazer NL Hayward C Hottenga JJ Jacobs KB Knowles JW Kutalik Z Monda KL Polasek O Preuss M Rayner NW Robertson NR Steinthorsdottir V Tyrer JP Voight BF Wiklund F Xu J Zhao JH Nyholt DR Pellikka N Perola M Perry JR Surakka I Tammesoo ML Altmaier EL Amin N Aspelund T Bhangale T Boucher G Chasman DI Chen C Coin L Cooper MN Dixon AL Gibson Q Grundberg E Hao K Juhani Junttila M Kaplan LM Kettunen J Koumlnig IR Kwan T Lawrence RW Levinson DF Lorentzon M McKnight B Morris AP Muumlller M Suh Ngwa J Purcell S Rafelt S Salem RM Salvi E Sanna S Shi J Sovio U Thompson JR Turchin MC Vandenput L Verlaan DJ Vitart V White CC Ziegler A Almgren P Balmforth AJ Campbell H Citterio L De Grandi A Dominiczak A Duan J Elliott P Elosua R Eriksson JG Freimer NB Geus EJ Glorioso N Haiqing S Hartikainen AL Havulinna AS Hicks AA Hui J Igl W Illig T Jula A Kajantie E Kilpelaumlinen TO Koiranen M Kolcic I Koskinen S Kovacs P Laitinen J Liu J Lokki ML Marusic A Maschio A Meitinger T Mulas A Pareacute G Parker AN Peden JF Petersmann A Pichler I Pietilaumlinen KH Pouta A Ridderstraringle M Rotter JI Sambrook JG Sanders AR Schmidt CO Sinisalo J Smit JH Stringham HM Bragi Walters G Widen E Wild SH Willemsen G Zagato L Zgaga L Zitting P Alavere H Farrall M McArdle WL Nelis M Peters MJ Ripatti S van Meurs JB Aben KK Ardlie KG Beckmann JS Beilby JP Bergman RN Bergmann S Collins FS Cusi D den Heijer M Eiriksdottir G Gejman PV Hall AS Hamsten A Huikuri HV Iribarren C Kaumlhoumlnen M Kaprio J Kathiresan S Kiemeney L Kocher T Launer LJ Lehtimaumlki T Melander O Mosley TH Jr Musk AW Nieminen MS ODonnell CJ Ohlsson C Oostra B Palmer LJ Raitakari O Ridker PM Rioux JD Rissanen A Rivolta C Schunkert H Shuldiner AR Siscovick DS Stumvoll M Toumlnjes A Tuomilehto J van Ommen GJ Viikari J Heath AC Martin NG Montgomery GW Province MA Kayser M Arnold AM Atwood LD Boerwinkle E Chanock SJ Deloukas P Gieger C Groumlnberg H Hall P Hattersley AT Hengstenberg C Hoffman W Lathrop GM Salomaa V Schreiber S Uda M Waterworth D Wright AF Assimes TL Barroso I Hofman A Mohlke KL Boomsma DI Caulfield MJ Cupples LA Erdmann J Fox CS Gudnason V Gyllensten U Harris TB Hayes RB Jarvelin MR Mooser V Munroe PB Ouwehand WH Penninx BW Pramstaller PP Quertermous T Rudan I Samani NJ Spector TD Voumllzke H Watkins H Wilson JF Groop LC Haritunians T Hu FB Kaplan RC Metspalu A North KE Schlessinger D Wareham NJ Hunter DJ OConnell JR Strachan DP Wichmann HE Borecki IB van Duijn CM Schadt EE Thorsteinsdottir U Peltonen L Uitterlinden AG Visscher PM Chatterjee N Loos RJ Boehnke M McCarthy MI Ingelsson E Lindgren CM Abecasis GR Stefansson K Frayling TM Hirschhorn JN
Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen et alNature 2010 Oct 14467(7317)832-8
RISK SCORE METHOD
PROCAMFramingham Classical Risk factors
0
025
05
075
1
10 105 11 115 12 125 13 135
Risk Score
Pro
ba
bil
ity
no CHD CHD Set Specificity at
5 False Positive
in no-CAD
11 of men who get
CAD have baseline
score over cut-off
89 of the events that occurred over 10 years
would not be predicted by the score
Can we improve on this with genotypes
Whıch genes
to study
20
Genotype - smoking interactions
in risk score
Better than classical +
genotypes plt00001
Adding Environment-Genotype interactions
enhances (DOUBLES) risk prediction score
0
02
04
06
6 7 8 9 10 11 12
Risk score
pro
bab
ilit
y
no CHD CHD
EVEN BETTER
24 of cases
have score
over cut-off
5 FPR
Classical Risk factors + Genotypes + Smokıng
22
2001
Cui Y Wei QQ Park HK amp Lieber CM Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species Science 293 1289ndash1292 (2001)
ldquoDevices based on nanowires are emerging as a powerful platform for the direct detection of biological and chemical species including low concentrations of proteins and virusesrdquo 1st July 2006 Analytic Chemistry
No
rma
lise
d
con
du
ctan
ce c
han
ge
Figure 18 | taken from E Stern JF Klemic DA Routenberg PN Wyrembak DB
Turner-Evans AD Hamilton DA LaVan TM Fahmy and MA Reed Label-free
immunodetection with CMOS-compatible semiconducting nanowires Nature 445
05498 (2007)
Born April 2014
Nanowire chip
DNA extraction
PCR
ldquoHandheldrdquo
Arrived from the engineers at A Star Singapore LAST WEEK
First cassettes Chloroquine resistant Malaria warfarin BRAF
tumour marker
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated
We discover one of the genes and call it BYH1 somebody would suggest using it for disease
prediction
T T T T
T T
T T
H
T
H
H
H
H
H H H
H
H
H
H H
H H
H H H H H H T T T
T
T
T T T T
T T
H
H H H T
T
T
H H H
H H H
H T T T
T T
T T
T T
4 3 2 1 0
average short Very
short tall
Very
tall
Always bump
your head
Often bump
Your head
ldquohundreds of variants in at least 180 loci influence human heightrdquo
Nature 2010 Oct 14467(7317)832-8 doi 101038nature09410 Epub 2010 Sep 29 Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen H1 Estrada K Lettre G Berndt SI Weedon MN Rivadeneira F Willer CJ Jackson AU Vedantam S Raychaudhuri S Ferreira T Wood AR Weyant RJ Segregrave AV Speliotes EK Wheeler E Soranzo N Park JH Yang J Gudbjartsson D Heard-Costa NL Randall JC Qi L Vernon Smith A Maumlgi R Pastinen T Liang L Heid IM Luan J Thorleifsson G Winkler TW Goddard ME Sin Lo K Palmer C Workalemahu T Aulchenko YS Johansson A Zillikens MC Feitosa MF Esko T Johnson T Ketkar S Kraft P Mangino M Prokopenko I Absher D Albrecht E Ernst F Glazer NL Hayward C Hottenga JJ Jacobs KB Knowles JW Kutalik Z Monda KL Polasek O Preuss M Rayner NW Robertson NR Steinthorsdottir V Tyrer JP Voight BF Wiklund F Xu J Zhao JH Nyholt DR Pellikka N Perola M Perry JR Surakka I Tammesoo ML Altmaier EL Amin N Aspelund T Bhangale T Boucher G Chasman DI Chen C Coin L Cooper MN Dixon AL Gibson Q Grundberg E Hao K Juhani Junttila M Kaplan LM Kettunen J Koumlnig IR Kwan T Lawrence RW Levinson DF Lorentzon M McKnight B Morris AP Muumlller M Suh Ngwa J Purcell S Rafelt S Salem RM Salvi E Sanna S Shi J Sovio U Thompson JR Turchin MC Vandenput L Verlaan DJ Vitart V White CC Ziegler A Almgren P Balmforth AJ Campbell H Citterio L De Grandi A Dominiczak A Duan J Elliott P Elosua R Eriksson JG Freimer NB Geus EJ Glorioso N Haiqing S Hartikainen AL Havulinna AS Hicks AA Hui J Igl W Illig T Jula A Kajantie E Kilpelaumlinen TO Koiranen M Kolcic I Koskinen S Kovacs P Laitinen J Liu J Lokki ML Marusic A Maschio A Meitinger T Mulas A Pareacute G Parker AN Peden JF Petersmann A Pichler I Pietilaumlinen KH Pouta A Ridderstraringle M Rotter JI Sambrook JG Sanders AR Schmidt CO Sinisalo J Smit JH Stringham HM Bragi Walters G Widen E Wild SH Willemsen G Zagato L Zgaga L Zitting P Alavere H Farrall M McArdle WL Nelis M Peters MJ Ripatti S van Meurs JB Aben KK Ardlie KG Beckmann JS Beilby JP Bergman RN Bergmann S Collins FS Cusi D den Heijer M Eiriksdottir G Gejman PV Hall AS Hamsten A Huikuri HV Iribarren C Kaumlhoumlnen M Kaprio J Kathiresan S Kiemeney L Kocher T Launer LJ Lehtimaumlki T Melander O Mosley TH Jr Musk AW Nieminen MS ODonnell CJ Ohlsson C Oostra B Palmer LJ Raitakari O Ridker PM Rioux JD Rissanen A Rivolta C Schunkert H Shuldiner AR Siscovick DS Stumvoll M Toumlnjes A Tuomilehto J van Ommen GJ Viikari J Heath AC Martin NG Montgomery GW Province MA Kayser M Arnold AM Atwood LD Boerwinkle E Chanock SJ Deloukas P Gieger C Groumlnberg H Hall P Hattersley AT Hengstenberg C Hoffman W Lathrop GM Salomaa V Schreiber S Uda M Waterworth D Wright AF Assimes TL Barroso I Hofman A Mohlke KL Boomsma DI Caulfield MJ Cupples LA Erdmann J Fox CS Gudnason V Gyllensten U Harris TB Hayes RB Jarvelin MR Mooser V Munroe PB Ouwehand WH Penninx BW Pramstaller PP Quertermous T Rudan I Samani NJ Spector TD Voumllzke H Watkins H Wilson JF Groop LC Haritunians T Hu FB Kaplan RC Metspalu A North KE Schlessinger D Wareham NJ Hunter DJ OConnell JR Strachan DP Wichmann HE Borecki IB van Duijn CM Schadt EE Thorsteinsdottir U Peltonen L Uitterlinden AG Visscher PM Chatterjee N Loos RJ Boehnke M McCarthy MI Ingelsson E Lindgren CM Abecasis GR Stefansson K Frayling TM Hirschhorn JN
Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen et alNature 2010 Oct 14467(7317)832-8
RISK SCORE METHOD
PROCAMFramingham Classical Risk factors
0
025
05
075
1
10 105 11 115 12 125 13 135
Risk Score
Pro
ba
bil
ity
no CHD CHD Set Specificity at
5 False Positive
in no-CAD
11 of men who get
CAD have baseline
score over cut-off
89 of the events that occurred over 10 years
would not be predicted by the score
Can we improve on this with genotypes
Whıch genes
to study
20
Genotype - smoking interactions
in risk score
Better than classical +
genotypes plt00001
Adding Environment-Genotype interactions
enhances (DOUBLES) risk prediction score
0
02
04
06
6 7 8 9 10 11 12
Risk score
pro
bab
ilit
y
no CHD CHD
EVEN BETTER
24 of cases
have score
over cut-off
5 FPR
Classical Risk factors + Genotypes + Smokıng
22
2001
Cui Y Wei QQ Park HK amp Lieber CM Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species Science 293 1289ndash1292 (2001)
ldquoDevices based on nanowires are emerging as a powerful platform for the direct detection of biological and chemical species including low concentrations of proteins and virusesrdquo 1st July 2006 Analytic Chemistry
No
rma
lise
d
con
du
ctan
ce c
han
ge
Figure 18 | taken from E Stern JF Klemic DA Routenberg PN Wyrembak DB
Turner-Evans AD Hamilton DA LaVan TM Fahmy and MA Reed Label-free
immunodetection with CMOS-compatible semiconducting nanowires Nature 445
05498 (2007)
Born April 2014
Nanowire chip
DNA extraction
PCR
ldquoHandheldrdquo
Arrived from the engineers at A Star Singapore LAST WEEK
First cassettes Chloroquine resistant Malaria warfarin BRAF
tumour marker
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated
ldquohundreds of variants in at least 180 loci influence human heightrdquo
Nature 2010 Oct 14467(7317)832-8 doi 101038nature09410 Epub 2010 Sep 29 Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen H1 Estrada K Lettre G Berndt SI Weedon MN Rivadeneira F Willer CJ Jackson AU Vedantam S Raychaudhuri S Ferreira T Wood AR Weyant RJ Segregrave AV Speliotes EK Wheeler E Soranzo N Park JH Yang J Gudbjartsson D Heard-Costa NL Randall JC Qi L Vernon Smith A Maumlgi R Pastinen T Liang L Heid IM Luan J Thorleifsson G Winkler TW Goddard ME Sin Lo K Palmer C Workalemahu T Aulchenko YS Johansson A Zillikens MC Feitosa MF Esko T Johnson T Ketkar S Kraft P Mangino M Prokopenko I Absher D Albrecht E Ernst F Glazer NL Hayward C Hottenga JJ Jacobs KB Knowles JW Kutalik Z Monda KL Polasek O Preuss M Rayner NW Robertson NR Steinthorsdottir V Tyrer JP Voight BF Wiklund F Xu J Zhao JH Nyholt DR Pellikka N Perola M Perry JR Surakka I Tammesoo ML Altmaier EL Amin N Aspelund T Bhangale T Boucher G Chasman DI Chen C Coin L Cooper MN Dixon AL Gibson Q Grundberg E Hao K Juhani Junttila M Kaplan LM Kettunen J Koumlnig IR Kwan T Lawrence RW Levinson DF Lorentzon M McKnight B Morris AP Muumlller M Suh Ngwa J Purcell S Rafelt S Salem RM Salvi E Sanna S Shi J Sovio U Thompson JR Turchin MC Vandenput L Verlaan DJ Vitart V White CC Ziegler A Almgren P Balmforth AJ Campbell H Citterio L De Grandi A Dominiczak A Duan J Elliott P Elosua R Eriksson JG Freimer NB Geus EJ Glorioso N Haiqing S Hartikainen AL Havulinna AS Hicks AA Hui J Igl W Illig T Jula A Kajantie E Kilpelaumlinen TO Koiranen M Kolcic I Koskinen S Kovacs P Laitinen J Liu J Lokki ML Marusic A Maschio A Meitinger T Mulas A Pareacute G Parker AN Peden JF Petersmann A Pichler I Pietilaumlinen KH Pouta A Ridderstraringle M Rotter JI Sambrook JG Sanders AR Schmidt CO Sinisalo J Smit JH Stringham HM Bragi Walters G Widen E Wild SH Willemsen G Zagato L Zgaga L Zitting P Alavere H Farrall M McArdle WL Nelis M Peters MJ Ripatti S van Meurs JB Aben KK Ardlie KG Beckmann JS Beilby JP Bergman RN Bergmann S Collins FS Cusi D den Heijer M Eiriksdottir G Gejman PV Hall AS Hamsten A Huikuri HV Iribarren C Kaumlhoumlnen M Kaprio J Kathiresan S Kiemeney L Kocher T Launer LJ Lehtimaumlki T Melander O Mosley TH Jr Musk AW Nieminen MS ODonnell CJ Ohlsson C Oostra B Palmer LJ Raitakari O Ridker PM Rioux JD Rissanen A Rivolta C Schunkert H Shuldiner AR Siscovick DS Stumvoll M Toumlnjes A Tuomilehto J van Ommen GJ Viikari J Heath AC Martin NG Montgomery GW Province MA Kayser M Arnold AM Atwood LD Boerwinkle E Chanock SJ Deloukas P Gieger C Groumlnberg H Hall P Hattersley AT Hengstenberg C Hoffman W Lathrop GM Salomaa V Schreiber S Uda M Waterworth D Wright AF Assimes TL Barroso I Hofman A Mohlke KL Boomsma DI Caulfield MJ Cupples LA Erdmann J Fox CS Gudnason V Gyllensten U Harris TB Hayes RB Jarvelin MR Mooser V Munroe PB Ouwehand WH Penninx BW Pramstaller PP Quertermous T Rudan I Samani NJ Spector TD Voumllzke H Watkins H Wilson JF Groop LC Haritunians T Hu FB Kaplan RC Metspalu A North KE Schlessinger D Wareham NJ Hunter DJ OConnell JR Strachan DP Wichmann HE Borecki IB van Duijn CM Schadt EE Thorsteinsdottir U Peltonen L Uitterlinden AG Visscher PM Chatterjee N Loos RJ Boehnke M McCarthy MI Ingelsson E Lindgren CM Abecasis GR Stefansson K Frayling TM Hirschhorn JN
Hundreds of variants clustered in genomic loci and biological pathways affect human height Lango Allen et alNature 2010 Oct 14467(7317)832-8
RISK SCORE METHOD
PROCAMFramingham Classical Risk factors
0
025
05
075
1
10 105 11 115 12 125 13 135
Risk Score
Pro
ba
bil
ity
no CHD CHD Set Specificity at
5 False Positive
in no-CAD
11 of men who get
CAD have baseline
score over cut-off
89 of the events that occurred over 10 years
would not be predicted by the score
Can we improve on this with genotypes
Whıch genes
to study
20
Genotype - smoking interactions
in risk score
Better than classical +
genotypes plt00001
Adding Environment-Genotype interactions
enhances (DOUBLES) risk prediction score
0
02
04
06
6 7 8 9 10 11 12
Risk score
pro
bab
ilit
y
no CHD CHD
EVEN BETTER
24 of cases
have score
over cut-off
5 FPR
Classical Risk factors + Genotypes + Smokıng
22
2001
Cui Y Wei QQ Park HK amp Lieber CM Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species Science 293 1289ndash1292 (2001)
ldquoDevices based on nanowires are emerging as a powerful platform for the direct detection of biological and chemical species including low concentrations of proteins and virusesrdquo 1st July 2006 Analytic Chemistry
No
rma
lise
d
con
du
ctan
ce c
han
ge
Figure 18 | taken from E Stern JF Klemic DA Routenberg PN Wyrembak DB
Turner-Evans AD Hamilton DA LaVan TM Fahmy and MA Reed Label-free
immunodetection with CMOS-compatible semiconducting nanowires Nature 445
05498 (2007)
Born April 2014
Nanowire chip
DNA extraction
PCR
ldquoHandheldrdquo
Arrived from the engineers at A Star Singapore LAST WEEK
First cassettes Chloroquine resistant Malaria warfarin BRAF
tumour marker
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated
RISK SCORE METHOD
PROCAMFramingham Classical Risk factors
0
025
05
075
1
10 105 11 115 12 125 13 135
Risk Score
Pro
ba
bil
ity
no CHD CHD Set Specificity at
5 False Positive
in no-CAD
11 of men who get
CAD have baseline
score over cut-off
89 of the events that occurred over 10 years
would not be predicted by the score
Can we improve on this with genotypes
Whıch genes
to study
20
Genotype - smoking interactions
in risk score
Better than classical +
genotypes plt00001
Adding Environment-Genotype interactions
enhances (DOUBLES) risk prediction score
0
02
04
06
6 7 8 9 10 11 12
Risk score
pro
bab
ilit
y
no CHD CHD
EVEN BETTER
24 of cases
have score
over cut-off
5 FPR
Classical Risk factors + Genotypes + Smokıng
22
2001
Cui Y Wei QQ Park HK amp Lieber CM Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species Science 293 1289ndash1292 (2001)
ldquoDevices based on nanowires are emerging as a powerful platform for the direct detection of biological and chemical species including low concentrations of proteins and virusesrdquo 1st July 2006 Analytic Chemistry
No
rma
lise
d
con
du
ctan
ce c
han
ge
Figure 18 | taken from E Stern JF Klemic DA Routenberg PN Wyrembak DB
Turner-Evans AD Hamilton DA LaVan TM Fahmy and MA Reed Label-free
immunodetection with CMOS-compatible semiconducting nanowires Nature 445
05498 (2007)
Born April 2014
Nanowire chip
DNA extraction
PCR
ldquoHandheldrdquo
Arrived from the engineers at A Star Singapore LAST WEEK
First cassettes Chloroquine resistant Malaria warfarin BRAF
tumour marker
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated
Genotype - smoking interactions
in risk score
Better than classical +
genotypes plt00001
Adding Environment-Genotype interactions
enhances (DOUBLES) risk prediction score
0
02
04
06
6 7 8 9 10 11 12
Risk score
pro
bab
ilit
y
no CHD CHD
EVEN BETTER
24 of cases
have score
over cut-off
5 FPR
Classical Risk factors + Genotypes + Smokıng
22
2001
Cui Y Wei QQ Park HK amp Lieber CM Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species Science 293 1289ndash1292 (2001)
ldquoDevices based on nanowires are emerging as a powerful platform for the direct detection of biological and chemical species including low concentrations of proteins and virusesrdquo 1st July 2006 Analytic Chemistry
No
rma
lise
d
con
du
ctan
ce c
han
ge
Figure 18 | taken from E Stern JF Klemic DA Routenberg PN Wyrembak DB
Turner-Evans AD Hamilton DA LaVan TM Fahmy and MA Reed Label-free
immunodetection with CMOS-compatible semiconducting nanowires Nature 445
05498 (2007)
Born April 2014
Nanowire chip
DNA extraction
PCR
ldquoHandheldrdquo
Arrived from the engineers at A Star Singapore LAST WEEK
First cassettes Chloroquine resistant Malaria warfarin BRAF
tumour marker
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated
2001
Cui Y Wei QQ Park HK amp Lieber CM Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species Science 293 1289ndash1292 (2001)
ldquoDevices based on nanowires are emerging as a powerful platform for the direct detection of biological and chemical species including low concentrations of proteins and virusesrdquo 1st July 2006 Analytic Chemistry
No
rma
lise
d
con
du
ctan
ce c
han
ge
Figure 18 | taken from E Stern JF Klemic DA Routenberg PN Wyrembak DB
Turner-Evans AD Hamilton DA LaVan TM Fahmy and MA Reed Label-free
immunodetection with CMOS-compatible semiconducting nanowires Nature 445
05498 (2007)
Born April 2014
Nanowire chip
DNA extraction
PCR
ldquoHandheldrdquo
Arrived from the engineers at A Star Singapore LAST WEEK
First cassettes Chloroquine resistant Malaria warfarin BRAF
tumour marker
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated
Born April 2014
Nanowire chip
DNA extraction
PCR
ldquoHandheldrdquo
Arrived from the engineers at A Star Singapore LAST WEEK
First cassettes Chloroquine resistant Malaria warfarin BRAF
tumour marker
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated
ldquoHandheldrdquo
Arrived from the engineers at A Star Singapore LAST WEEK
First cassettes Chloroquine resistant Malaria warfarin BRAF
tumour marker
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated
First cassettes Chloroquine resistant Malaria warfarin BRAF
tumour marker
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated
Summary
bull Identification of monogenic causes of cancer increase service pressure but are economical where prevention is possible
bull DNA sequencing is now cheap bull We face variant inundation bull Power to predict common disease
is over-estimated bull Point of care testing has a place for
drug sensitivity tumour testing and infectious diseases
bull Predictive power of gene testing in polygenic traits is overstated