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SWR Leusden 30 januari 2015

Prof dr Gertjan van Ommen Biobanking and BioMolecular Research Infrastructure Centre for Medical Systems Biology

Leiden University Medical Centre

De groei(stuipen) van de genetica: Nederland als voortrekker

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TEST

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LATER: PERSONALIZED MEDICINE NOW: TRIAL AND ERROR

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PHARMACOGENOMICS: Genomics and biobank research into drug treatment outcomes

26-27 june 2000

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Title&

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Mammalian Genomes

Monodelphis, Opossum

Platypus!

Human Mouse, rat Chimpanzee Dog(s)

Photo seqsystem !

dec 2006

Sequencing in action

Human genomes

Craig Venter

James Watson

Individual genomes, may 2008:

ANONYMOUS: Yoruban male Yoruban trio

Asiatic genome Female Cancer

Marjolein Kriek, Clinical geneticist

Leiden

A human genome

By Academic Hospitalnot a large genome center, nor a company (sequence technology)

Marjolein KriekPhD, clinical geneticist (i.t.)

First : LUMC

Leiden Netherlands

EuropeFEMALE

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Australia&

Publieks&percep6e...&&

here the defective gene for parking a car backwards

Not everybody agreed…

Human and Clinical Genetics

Sequencing&kosten&

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Human and Clinical Genetics! © JT den Dunnen!

The human genome 2000

€ 2,000,000,000 in ~10 years

2008 € 50 - 100,000 in ~4 months

2010 € 5,000 in ~2 weeks

2013 € 2,000 in a day

...2020 ? € 10 ? ... in minutes ?

A million times cheaper AND 3000 x faster !!

Human and Clinical Genetics!

Oxford Nanopore3&

no labels !

~5% v.h. genoom onder selectie ~500,000 geconserveerde elementen

33%(=(eiwitcoderend((

67%(=(???(

DNA

Genen

GENEN

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DNA

Genen

GENEN

DNA

Genen

JUNK DNA?

Principal component analysis of European populations Simon Heath et al. (2008) EJHG 16, 1413 – 1429

1st principal component = 26% of variance

2nd p

rinci

pal c

omon

ent =

6%

of v

aria

nce

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Genomes in common diseases: What are we trying to accomplish?

Understand the biology behind any disease but also:

Improve diagnostic classification of common diseases

Understanding individual disease risks and response to therapies (positive and adverse)

Produce data useful for public health intervention strategies

Cumulative number of trait loci identified using GWA

0

100

200

300

400

500

600

700

800

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

year

loci

CDKN2B/AATG16L1

5p1310q21IRGM!

NKX2-3IL12B3p211q24

PTPN2TCF2

CDKN2B/AIGF2BP2CDKAL1

HHEXSLC30A8

MEIS1LBXCOR1BTBD9

C3ORMDL3

4q25TCF2GCKRFTO

C12orf30ERBB3

KIAA0350CD22616p13PTPN2SH2B3FGFR2TNRC9MAP3K1LSP1

LOXL1IL7R

TRAF1/C5STAT4ABCG8GALNT2PSRC1NCANTBL2TRIB1

KCTD10ANGLPT3GRIN3A

NOS1APIFIH1PCSK9CFB/C2

LOC3877158q24IL23RTCF7L2

CD25IRF5

PCSK9CFHPTPN22KCNJ11CTLA4IBD5

NOD2PPARγ

e.g.:High Cholesterol

ObesityStature

Myocardial infarctArrhythmias

Type 2 Diabetes Prostate cancerBreast cancerColon cancer

Bipolar disorderSchizophrenia

Age Related Macular DegenerationCrohns DiseaseType 1 Diabetes

Systemic Lupus ErythematosusAsthma

Restless leg syndromeGallstone diseaseMultiple sclerosis

Rheumatoid arthritisGlaucoma

NHGRI(GWA(Catalog(www.genome.gov/GWAStudies(www.ebi.ac.uk/fgpt/gwas/((

Published(GenomeJWide(AssociaKons(through(12/2013(Published(GWA(at(p≤5X10J8(for(17(trait(categories(

We need more studies of well characterized human populations

Help to expose both common and rare risk variants, highly relevant for human health

Guide us to novel functional domains in the landscape of human genome

Critical in efforts to define the significance of genetic and life style risk factors

Contribute to the functional annotation of genome Provide the basis for future health care decisions

by our societies

- 5 3 5 2

5 0 3 5 5 5

5 5 5 3 5 5 5

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Biobanking and Biomolecular Research Infrastructure - NL

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BBMRI#NL:&CONNECTIVITY&

TWIN(Registry(

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COHORTS(#&Outbred&#&Isolates&

Onset,$causality$Mul8$uses$$

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CaseJcontrol(Sample&sets&High$disease$$frequency$

The(Netherlands(:(200(biobanks(–(800.000(samples((~(5%!)(

c& Wageningen

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Table(of(Contents(for(The$American$Journal$of$Human$Gene3cs,(Volume(87,(Issue(3.(September(2010(Editors'(Corner(This(Month(in(The$Journal&K.D.&Bungartz&and&R.E.&Williamson(This(Month(in(GeneKcs&K.B.&Garber(Book(ReviewA(Guide(to(GeneKc(Counseling,(2nd(EdiKon&M.&Fox&((SEPTEMBER(2010(

Direct(Measure(of(the(De(Novo(MutaKon(Rate(in(AuKsm(and(Schizophrenia(CohortsP.&Awadalla,&J.&Gauthier,&R.A.&Myers,&F.&Casals,&F.F.&Hamdan,&A.R.&Griffing,&M.&Côté,&E.&Henrion,&D.&Spiegelman,&J.&Tarabeux,&A.&Piton,&Y.&Yang,&A.&Boyko,&C.&Bustamante,&L.&Xiong,&J.L.&Rapoport,&A.M.&Addington,&J.L.E.&DeLisi,&M.#O.&Krebs,&R.&Joober,&B.&Millet,&É&.&&Fombonne,&L.&Moaron,&M.&Zilversmit,&J.&Keebler,&H.&Daoud,&C.&Marineau,&M.#H.&Roy#Gagnon,&M.#P.&Dubé,&A.&Eyre#Walker,&P.&Drapeau,&E.A.&Stone,&R.G.&Lafrenière,&and&G.A.&Rouleau(BOOST:(A(Fast(Approach(to(DetecKng(GeneJGene(InteracKons(in(GenomeJwide(CaseJControl(StudiesX.&Wan,&C.&Yang,&Q.&Yang,&H.&Xue,&X.&Fan,&N.L.S.&Tang,&and&W.&Yu((Mutability(of(YJChromosomal(Microsatellites:(Rates,(CharacterisKcs,(Molecular(Bases,(and(Forensic(ImplicaKonsK.N.&Ballantyne,&M.&Goedbloed,&R.&Fang,&O.&Schaap,&O.&Lao,&A.&Wollstein,&Y.&Choi,&K.&van&Duijn,&M.&Vermeulen,&S.&Brauer,&R.&Decorte,&M.&Poetsch,&N.&von&Wurmb#Schwark,&P.&de&Knijff,&D.&Labuda,&H.&Vézina,&H.&Knoblauch,&R.&Lessig,&L.&Roewer,&R.&Ploski,&T.&Dobosz,&L.&Henke,&J.&Henke,&M.R.&Furtado,&and&M.&Kayser(Reports(

Recessive(MutaKons(in(the(Gene(Encoding(the(Tight(JuncKon(Protein(Occludin(Cause(BandJlike(CalcificaKon(with(Simplified(GyraKon(and(PolymicrogyriaM.C.&O'Driscoll,&S.B.&Daly,&J.E.&Urquhart,&G.C.M.&Black,&D.T.&Pilz,&K.&Brockmann,&M.&McEntagart,&G.&Abdel#Salam,&M.&Zaki,&N.I.&Wolf,&R.L.&Ladda,&S.&Sell,&S.&D'Arrigo,&W.&Squier,&W.B.&Dobyns,&J.H.&Livingston,&and&Y.J.&Crow&(TBC1D24,(an(ARF6JInteracKng(Protein,(Is(Mutated(in(Familial(InfanKle(Myoclonic(EpilepsyA.&Falace,&F.&Filipello,&V.&La&Padula,&N.&Vanni,&F.&Madia,&D.&De&Pietri&Tonelli,&F.A.&de&Falco,&P.&Striano,&F.&Dagna&Bricarelli,&C.&Minek,&F.&Benfena6,&A.&Fassio,&and&F.&Zara&&A(Focal(Epilepsy(and(Intellectual(Disability(Syndrome(Is(Due(to(a(MutaKon(in((TBC1D24$M.A.&Corbea,&M.&Bahlo,&L.&Jolly,&Z.&Afawi,&A.E.&Gardner,&K.L.&Oliver,&S.&Tan,&A.&Coffey,&J.C.&Mulley,&L.M.&Dibbens,&W.&Simri,&A.&Shalata,&S.&Kivity,&G.D.&Jackson,&S.F.&Berkovic,&and&J.&Gecz(Nonsense(MutaKons(in(FAM161A(Cause(RP28JAssociated(Recessive(ReKniKs(PigmentosaT.&Langmann,&S.A.&Di&Gioia,&I.&Rau,&H.&Stöhr,&N.S.&Maksimovic,&J.C.&Corbo,&A.B.&Renner,&E.&Zrenner,&G.&Kumaramanickavel,&M.&Karlsteaer,&Y.&Arsenijevic,&B.H.F.&Weber,&A.&Gal,&and&C.&Rivolta&&Homozygosity(Mapping(Reveals(Null(MutaKons(in&FAM161A(as(a(Cause(of(AutosomalJRecessive(ReKniKs(PigmentosaD.&Bandah#Rozenfeld,&L.&Mizrahi#Meissonnier,&C.&Farhy,&A.&Obolensky,&I.&Chowers,&J.&Pe'er,&S.&Merin,&T.&Ben#Yosef,&R.&Ashery#Padan,&E.&Banin,&and&D.&Sharon(((

MutaKons(in(DHDPSL(Are(Responsible(For(Primary(Hyperoxaluria(Type(IIIR.&Belostotsky,&E.&Seboun,&G.H.&Idelson,&D.S.&Milliner,&R.&Becker#Cohen,&C.&Rinat,&C.G.&Monico,&S.&Feinstein,&E.&Ben#Shalom,&D.&Magen,&I.&Weissman,&C.&Charon,&and&Y.&Frishberg(A(MutaKon(in(ZNF513,(a(PutaKve(Regulator(of(Photoreceptor(Development,(Causes(AutosomalJRecessive(ReKniKs(PigmentosaL.&Li,&N.&Nakaya,&V.R.M.&Chavali,&Z.&Ma,&X.&Jiao,&P.A.&Sieving,&S.&Riazuddin,&S.I.&Tomarev,&R.&Ayyagari,&S.A.&Riazuddin,&and&J.F.&Hejtmancik(MutaKons(in&ABHD12(Cause(the(NeurodegeneraKve(Disease(PHARC:(An(Inborn(Error(of(Endocannabinoid(MetabolismT.&Fiskerstrand,&D.&H'mida#Ben&Brahim,&S.&Johansson,&A.&M'zahem,&B.I.&Haukanes,&N.&Drouot,&J.&Zimmermann,&A.J.&Cole,&C.&Vedeler,&C.&Bredrup,&M.&Assoum,&M.&Tazir,&T.&Klockgether,&A.&Hamri,&V.M.&Steen,&H.&Boman,&L.A.&Bindoff,&M.&Koenig,&and&P.M.&Knappskog(Exome&Sequencing&Iden6fies&WDR35&Variants&Involved&in&Sensenbrenner&Syndrome&Chris6an&Gilissen,&Heleen&H.&Arts,&Alexander&Hoischen,&Liesbeth&Spruijt,&Dorus&A.&Mans,&Peer&Arts,&Bart&van&Lier,&Marloes&Steehouwer,&Jeroen&van&Reeuwijk,&Sarina&G.&Kant,&Ronald&Roepman,&Nine&V.A.M.&Knoers,&Joris&A.&Veltman,&Han&G.&Brunner&

Dominant(MutaKons(in&RP1L1(Are(Responsible(for(Occult(Macular(DystrophyM.&Akahori,&K.&Tsunoda,&Y.&Miyake,&Y.&Fukuda,&H.&Ishiura,&S.&Tsuji,&T.&Usui,&T.&atase,&M.&Nakamura,&H.&Ohde,&T.&Itabashi,&H.&Okamoto,&Y.&Takada,&and&T.&Iwata(A(Locus(on(Chromosome(1p36(Is(Associated(with(Thyrotropin(and(Thyroid(FuncKon(as(IdenKfied(by(GenomeJwide(AssociaKon(StudyV.&Panicker,&S.G.&Wilson,&J.P.&Walsh,&J.B.&Richards,&S.J.&Brown,&J.P.&Beilby,&A.P.&Bremner,&G.L.&Surdulescu,&E.&Qwei6n,&I.&Gillham#Nasenya,&N.&Soranzo,&E.M.&Lim,&S.J.&Fletcher,&and&T.D.&Spector(Protein(Tyrosine(Phosphatase(PTPN14(Is(a(Regulator(of(LymphaKc(FuncKon(and(Choanal(Development(in(HumansA.C.&Au,&P.A.&Hernandez,&E.&Lieber,&A.M.&Nadroo,&Y.#M.&Shen,&K.A.&Kelley,&B.D.&Gelb,&and&G.A.&Diaz&&JULY(2010(

Whole&Exome&Sequencing&and&Homozygosity&Mapping&Iden6fy&Muta6on&in&the&Cell&Polarity&Protein&GPSM2&as&the&Cause&of&Nonsyndromic&Hearing&Loss&DFNB82.&Tom&Walsh,&Hashem&Shahin,&Tal&Elkan#Miller,&Ming&K.&Lee,&Anne&M.&Thornton,&Wendy&Roeb,&Amal&Abu&Rayyan,&Suheir&Loulus,&Karen&B.&Avraham,&Mary#Claire&King,&Moien&Kanaan(

Terminal&Osseous&Dysplasia&Is&Caused&by&a&Single&Recurrent&Muta6on&in&the&FLNA&Gene&(Exome&Sequencing)&Yu&Sun,&Rowida&Almomani,&Emmelien&Aten,&Jacopo&Celli,&Jaap&van&der&Heijden,&Hanka&Venselaar,&Stephen&P.&Robertson,&Anna&Baroncini,&Brunella&Franco,&Lina&Basel#Vanagaite,&Emiko&Horii,&Ricardo&Drut,&Yavuz&Ariyurek,&Johan&T.&den&Dunnen,&Mar6jn&H.&Breuning&

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DIRECTE(BENEFIT(:(DIAGNOSTIEK(EN(BEGRIP(VAN(ZELDZAME(ZIEKTEN(((((((((((((((((((((((((((((((((((((

Bridging&common&and&rare&disease&Rare&to&common&•  Excellent&human&models&for&therapy&development:&&•  & #&one&knows&what&one&should&see&when&it&works&!&•  & #&extended&use&later&&•  Therapy&business&models&more&viable&than&thought&•  Next&gen&sequencing&causes&rapid&advances,&new&therapies&•  !&Large,$wellAinformed$and$organized$pa8ent$cons8tuency$&Common&to&rare&•  Splikng&up&of&fields&in&rarer&subclasses&•  More&homogeneous&subgroups:&

•  Smaller,&cheaper,&shorter&trials&•  Longer&cost&recovery&period&under&patent&

•  !&Large$biobanks$needed$for$recruitment$of$small$subgroups$$

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After HumanGenome Project

Basic tools exist tocharacterize the biology

behind human diseases

DE TOEKOMST?

Trait Risk schizofrenie 2x Dopamine receptor D4.2+ rheuma >65j 18% hartfalen 22% hoge bloeddruk 8% long kanker 27% prostaat kanker 12% darm kanker 10% leukemie 7% huid kanker 4% borst/ovarium kanker 0% suicide 6% IQ A+B-C0D*...Q+…Z23a (etc.)

DETERMINISME -> PROBABILISME

SCHIZOPHRENIE

1% in de populatie

Erfelijke factor met 2x risico:

98% kans om het NIET te krijgen

… als je WEL het risico-gen hebt!

Data&Protec6on&..&

Acknowledgements(GoNL(team((

Paul&&de&Bakker&

Cornelia&Van&Duijn& Morris&

Swertz&

Cisca&Wijmenga&

Dorret&Boomsma&

Eline&Slagboom&

Gertjan&Van&Ommen&

Credits,&thanks,&acknowledgements:&Steering group UMCG: Cisca Wijmenga (PI), Morris Swertz; LUMC: Gertjan van Ommen, Eline Slagboom; Jasper Bovenberg (ELSI); EMC: Cornelia van Duijn; VUmc: Dorret Boomsma; UMCU: Paul de Bakker

Cohort collection and sample management LUMC: Eline Slagboom, Ton de Craen, Marian Beekman; VUmc: Dorret Boomsma; UMCG: Bruce Wolffenbuttel, Mathieu Platteel; EMC: Bert Hofman

Sequencing BGI: Yuanping Du, Ruoyan Chen, Hongzhi Cao, Rui Cao, Yushen Sun, Jeremy Sujie Cao

Data processing and Analysis (Rainbow project 2) UMCG: Morris Swertz (Co-Chair), Freerk van Dijk, Pieter Neerincx, Martijn Dijkstra; AMC: Mark Santcroos, Barbera van Schaik; LUMC: Jan Bot, Kai Ye, Eric-Wubbo Lameijer, Martijn Vermaat, Jeroen Laros; EMC: Slavik Koval, Lennart Karssen, Karol Estrada, Elisa van Leeuwen, Karol Estrada, Fernando Rivadeneira; UMCN: Jayne Hehir, Joep Ligt, VUmc: Jouke-Jan Hottenga, Matthijs Kattenberg; NBIC: David van Enckevort, Leon Mei; UMCU/Hubrecht: Laurent Francioli, Wigard Kloosterman, Ies Nijman, Victor Guryev, Paul de Bakker (Co-Chair)

Collaborators Broad: Shamil Sunyaev, Adam Kiezun, Steve McCarroll, Bob Handsaker, Mark Depristo and GSA Team; U Wash: Evan Eichler; Columbia: Itsik Pe’er; U Penn: Ben Voight

Other collaborators Target Consortium, CIT Rekencentrum, BigGrid