Download ICSB3: DRPM Measures

Genome+Environment
= Traits, [diseases],
(treatments)
1933
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)
SNP chip vs Sequence : Breast Cancer
2x (1Mbp vs 3000Mbp)
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
2
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
3
Prioritizing by odds ratio, actionability, FP consequences
Common Disease – Common Variant
Theory. How common?
ApoE allele e4 : Alzheimer’s dementia,
& hypercholesterolemia
15% in humans, >97% in chimps
HbS 17% & G6PD 40% in a Saudi sample
CCR5D32 : resistance to HIV
9% in caucasians
One form of HIV-1 Resistance
Association test for CCR-5 & HIV resistance
Alleles
CCR-5+
D ccr-5
total
Obs Neg ObsSeroPos total
ExpecNeg ExpecPos
1278
1368
2646
1305
1341
130
78
208
103
105
1408
1446
2854
dof=(r-1)(c-1)=1
ChiSq=sum[(o-e)^2/e]=
15.6
P
0.00008
Samson et al. Nature 1996 382:722-5
But what if we test more than one locus?
Y= Number of Sib Pairs (Assocation)
X= Number of Alleles (Hypotheses) Tested
Y= Number of Sib Pairs (Association)
X= Population frequency (p)
GRR=1.5, p= 0.5 (population frequency)
GRR=1.5, #alleles=1E6
1,600
1,400
1E+10
1,200
1E+9
1,000
1E+8
800
600
1E+7
[based on Risch & Merikangas
(1996) Science 273: 1516]
|
400
1E+6
200
1E+5
0
[based on Risch & Merikangas
(1996) Science 273: 1516]
1E+4
1E+4
1E+6
1E+8
1E+10
1E+12
1E+14
1E+16
1E+18
1E+20
1E+22
1E+3
|
Y= Number of Sib Pairs (Association)
X= Genotypic Relative Risk (GRR)
1E+2
1
0.1
0.01
0.001
0.0001 0.00001
1E-06
1E-07
1E-08
1E-09
#alleles=1E6, p=0.5 (population frequency)
1E+8
The future of genetic studies
of complex human diseases.
Ref (Note above graphs are
active spreadsheets -- just click)
1E+7
1E+6
[based on Risch &
Merikangas (1996)
|
Science 273: 1516]
1E+5
1E+4
1E+3
1E+2
GRR = Genotypic relative risk
|
1E+1
0.001
0.01
1.001
0.1
1.01
1
1.1
2
10
11
100
101
1000
1,001
10,001
10000
1-GRR
GRR