Genome+Environment = Traits, [diseases], (treatments) Hair: Baldness [alopecia](minoxidil) Eyes: [Near/Far-sightedness](glasses) Iris color [ARMD] (glasses)

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