Genome+Environment = Traits, [diseases], (treatments)
Hair: Baldness [alopecia](minoxidil) Eyes: [Near/Far-sightedness](glasses)
Iris color [ARMD] (glasses)Face: [Developmental syndromes, Wrinkles] (Botox)
Brain: ADHD(Ritalin); Depression(Prozac); Headache(analgesics)Sleep & Circadian (caffeine, amphetamine, modafinil)
Motion sickness (Dramamine, and Scopolamine)Ears: Sensitivity (hearing aids)
Nose: Shape [breathing disorders] (CPAP)Lip: [Cleft palate] (surgery); [Hirsutism] (calcium thioglycolate)
Mouth: Halitosis, throat exams; aerosols [airborne pathogens]Digestion [reflux, gas,ulcer] (antibiotics, antacids, PPIs)
Back: Strain sensitivity [IDD] (analgesics)Skin: Perspiration, Body odor, Pheromones (deodorants)
Surface texture [psoriasis] (topicals, photo-treatments)Immune components [acne] (topical antibiotics)
Skin color [vitamin D & sunburn] (supplements, SPF cream)Hands: Dermatoglyphics [syndromes], [Arthritis](corticosteroids)
Internal sensors: Proprioceptor, Repetitive stress (NSAIAs)Body: Height [Marfan] [short stature] (hGH)
Weight [anorexia] [obesity] (Orlistat, Phentermine, Sibutramine)Allergies (antihistamines, cortisone, epinephrine, theophylline)
Metabolic polymorphisms (vitamins, minerals, insulin)Feet: Plantar fasciitis (orthotic shoes)
Athlete’s foot (miconazole, itraconazole, terbinafine, salicylate)1933
2
SNP chip vs Sequence : Breast Cancer
deCODEme: “does not include the high-risk but rare BRCA1 and BRCA2 breast cancer risk variants”.
Navigenics: “Mutations in BRCA1 or BRCA2 are less common in the population and are only present in approximately 5 – 10% of
families with breast and ovarian cancer.”23andme: “Hundreds of cancer-associated BRCA1 and BRCA2
mutations have been documented, but three specific BRCA mutations are worthy of note because they are responsible for a
substantial fraction of hereditary breast cancers and ovarian cancers among women with Ashkenazi Jewish ancestry”.
Knome: Nearly complete genome sequence
2x (1Mbp vs 3000Mbp)
3
Valuable Personal Genome Sequences
1526 genes are highly predictive & medically actionable (inherited & cancer) at ~$2K per gene. PKU, Tay Sachs, Cystic Fibrosis, BRCA1/2, etc.(See Genetests.org)
Pharmacogenomic drug/allele combinations:Herceptin, Iressa, ..
Also: Ancestry, Forensics, Social Networking, Education, Research
Prioritizing by odds ratio, actionability, FP consequences
Common Disease – Common Variant Theory. How common?
ApoE allele 4 : Alzheimer’s dementia, & hypercholesterolemia15% in humans, >97% in chimps
HbS 17% & G6PD 40% in a Saudi sample
CCR532 : resistance to HIV 9% in caucasians
One form of HIV-1 Resistance
Association test for CCR-5 & HIV resistanceAlleles Obs Neg ObsSeroPos total ExpecNeg ExpecPosCCR-5+ 1278 1368 2646 1305 1341 ccr-5 130 78 208 103 105total 1408 1446 2854
Pdof=(r-1)(c-1)=1 ChiSq=sum[(o-e) 2̂/e]= 15.6 0.00008
Samson et al. Nature 1996 382:722-5
But what if we test more than one locus?
The future of genetic studies of complex human diseases. Ref (Note above graphs are active spreadsheets -- just click)
Y= Number of Sib Pairs (Association)X= Population frequency (p)
GRR=1.5, #alleles=1E6
1E+2
1E+3
1E+4
1E+5
1E+6
1E+7
1E+8
1E+9
1E+10
1E-091E-081E-071E-060.000010.00010.0010.010.11
[based on Risch & Merikangas (1996) Science 273: 1516]
| Y= Number of Sib Pairs (Association)X= Genotypic Relative Risk (GRR)
#alleles=1E6, p=0.5 (population frequency)
1E+1
1E+2
1E+3
1E+4
1E+5
1E+6
1E+7
1E+8
0.001 0.01 0.1 1 10 100 1000 10000
1.001 1.01 1.1 2 11 101 1,001 10,001
1-GRRGRR
[based on Risch & Merikangas (1996) Science 273: 1516]|
|
Y= Number of Sib Pairs (Assocation)X= Number of Alleles (Hypotheses) Tested
GRR=1.5, p= 0.5 (population frequency)
0
200
400
600
800
1,000
1,200
1,400
1,600
1E+4 1E+6 1E+8 1E+10 1E+12 1E+14 1E+16 1E+18 1E+20 1E+22
[based on Risch & Merikangas (1996) Science 273: 1516]|
GRR = Genotypic relative risk