1. Genome-wide Associations
Lakshmi K Matukumalli

2. Illumina SNP Genotyping
Chemistry
Genotype Data

3. Fine Mapping with SNP Markers
Advantages of SNPs as genetic markers
as compared to microsatellites.
High abundance
Distribution throughout the genome
Ease of genotyping
Improved accuracy
Availability of high throughput
multiplex genotyping platforms

4. Objectives for GWA Create Cures for Diseases (Humans)
Localize diseases to narrow chromosomal regions
Identify causative mutations for disease
Genetic predisposition to drugs / diseases
Personalized medicine
Selection Decisions (Live stock & Plants)
Increased productivity, disease resistance, composition (Fat, protein, tenderness)
Identification of QTL regions
Application of Marker assisted selection
Genome Selection

5. Traditional Methods time present LINKAGE MAPPING
QTL
LINKAGE MAPPING
Where genes are mapped by typing genetic markers in families to identify regions that are associated with disease or trait values within pedigrees more often than are expected by chance. Such linked regions are more likely to contain a causal genetic variant.
ADMIXTURE MAPPING
Predicting the recent ancestry of chromosomal segments across the genome to identify regions for which recent ancestry in a particular population correlates with disease or trait values. Such regions are more likely to contain causal variants that are more common in the ancestral population.
PENETRANCE
The proportion of individuals with a specific genotype who manifest the genotype at the phenotypic level. For example, if all individuals with a specific disease genotype show the disease phenotype, then the genotype is said to be 'completely penetrant'.
HERITABILITY
The proportion of the variation in a given characteristic or state that can be attributed to (additive) genetic factors.
Emergence of Variations Over Time
Common Ancestor
time
present

6. Linkage Mapping Non-Parametric Linkage Transmission Disequilibrium
Test (TDT)

7. Genome Wide Association
Principles
Fisher’s theory of additive effects of common alleles
* Human heterozygosity is attributed to common ancestral variants
(CDCV Common disease common variant hypothesis)
* Variants influencing common late onset diseases of modernity may not have been subject to purifying selection

9. Whole Genome Prediction
Fit haplotype block into a statistical model:
Effect A B C D E F G H I J K L M 1 1 1 1 1 1 1 1 1 1 1 1 1 1
Levels 2 2 2 2 2 2 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 4 4 4 4

10. Genome Enhanced PBV Block GEPBV Haplotype A B C D 1 +0.01 +1.03 -1.23
+6.35 2
+0.06
-0.74
+0.98
+2.19 3
+0.05 4
-8.59
Animal 1
1 1
1 2
2 2
1 3
0.01
1.03
0.98
6.35
8.67
Animal 2
2 4
0.06
2.19
-2.26

11. Genome Wide Association - Methods
Gene centric approach
Non-ascertained (Uniformly spaced / Tag SNPs)

13. Age-Related Macular Degeneration
Complement Factor H Polymorphism

14. Samples
1,464 Patients T2D
1,464 Case Controls
Traits
Glucose metabolism
Lipids
Obesity
Blood pressure
Follow-up
107 SNPs on extreme p-values genotyped on 10, 850 additional populations

15. Type 2 diabetes and triglyceride levels
T2D
non-coding region near CDKN2A and CDKN2B
Intron of IGF2BP2
Intron of CDKAL1
Triglycerides
Intron of glucokinase regulatory protein

16. Coronary Heart Disease
375,00 SNPs
WTCCC
1926 Case
2938 Controls
German GI Family
875 Case
1644 Control
Genotyping by candidate gene approach

17. Significant Associations
9p21.3 region
P=1.80 x 10(-14) WTCCC
P=3.40 x 10(-6), German MI Family.
The WTCCC study revealed nine loci that were strongly associated with coronary artery disease (P<1.2 x 10(-5)) and less than a 50% chance of being falsely positive). Two additional loci at 6q25.1 and 2q36.3 were also successfully replicated in the German study:
The combined analysis of the two studies identified four additional loci significantly associated with coronary artery disease (P<1.3 x 10(-6))) and a high probability (>80%) of a true association: chromosomes 1p13.3, 1q41, 10q11.21, and 15q22.33.

18. GWA of seven Common Diseases
14,000 Cases
(2,000 each)
3,000 shared controls

19. Determining Marker Order
Clones
Chromosome segments
Genotyping
A BC D E F G

20. Positive Natural Selection
Neutral Evolution
Versus
Positive Natural Selection