Lecture 20 - Association Tests

• Gibson and Muse, Chapt. 3, 2nd Ed.

Association Populations

• Case-Control - unstructured populations

• Family-Based - structured populations

• Continuous variable - structured and/or unstructured

Pitfalls of Association Tests• Trait h2

• Number of genes effecting trait• Penetrance and expressivity• Extent and uniformity of LD• Genetic heterogeneity• Population stratification• Admixture• Hidden environmental structure• GxE and GxG• Incomplete genotyping

M4

Genomewide AssociationModel-Free & Unbiased

M1 M2 M3 M5

cases

M1 M2 M3 M5

controls

M4

causal mutation

Pug Dog EncephalitisA canine model of Multiple Sclerosis?

• CNS Inflammation & Necrosis

• Early Onset = 1.5 yrs

• Fatal = 3 weeks

• Complex Inheritance

M1 M2 M3 M4 M5 M1 M2 M3 M4 M5

cases controls

Pug Dog EncephalitisA canine model of Multiple Sclerosis?

SNP 1 SNP 2 SNP 3 Trait 1 Trait 2AT GT CC 1 3AT GT GG 10 4TT TT GG 10 7AA GG CG 5 1AA GG CG 5 3AT TT CG 5 5AA GT CC 1 2TT GT GG 10 8TT TT GG 10 7TT TT CC 1 10AT GG CG 5 6AA GT CG 5 4AA TT CG 5 1TT TT GG 10 9AT GG CC 1 6AT GT CG 5 4AT GG CC 1 5AA GG CC 1 2AA GG GG 10 1TT GT GG 10 8

SNP 1 SNP 2 SNP 3 Trait 1 Trait 2AT GT CC 1 3AT GT GG 10 4TT TT GG 10 7AA GG CG 5 1AA GG CG 5 3AT TT CG 5 5AA GT CC 1 2TT GT GG 10 8TT TT GG 10 7TT TT CC 1 10AT GG CG 5 6AA GT CG 5 4AA TT CG 5 1TT TT GG 10 9AT GG CC 1 6AT GT CG 5 4AT GG CC 1 5AA GG CC 1 2AA GG GG 10 1TT GT GG 10 8

f(AA)=0.35 f(GG)=0.35 f(CC)=0.30f(AT)=0.35 f(GT)=0.35 f(CG)=0.45f(TT)=0.30 f(GG)=0.30 f(GG)=0.25

Trait 1 Trait 1 Trait 1u(AA)=32/7=4.57 u(GG)=28/7=4.00 u(CC)=6/6=1.00u(AT)=23/6=3.83 u(GT)=42/7=6.00 u(GC)=35/7=5.00u(TT)=51/6=8.50 u(TT)=41/6=6.83 u(GG)=70/7=10.00

Trait 2 Trait 2 Trait 2u(AA)=14/7=2.00 u(GG)=24/7=3.43 u(CC)=28/6=4.66u(AT)=33/7=4.71 u(GT)=33/7=4.71 u(GC)=24/7=3.43u(TT)=49/6=8.16 u(TT)=41/6=6.83 u(GG)=44/7=6.28

A Review• Lecture 11 - ESTs• Lecture 12 - Genetic markers• Lecture 13 - Genetic mapping• Lecture 14 - Complex traits• Lecture 15 - QTL mapping• Lecture 16 - SNP discovery• Lecture 17 - Nucleotide diversity and LD

• Lecture 18 - Tests for selection• Lecture 19 - SNP genotyping• Lecture 20 - Association mapping