Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies
description
Transcript of Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies
![Page 1: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/1.jpg)
Genetics for Epidemiologists
Lecture 5: Analysis of Genetic Association Studies
National Human Genome Research
Institute
National Institutes of
Health
U.S. Department of Health and
Human Services
U.S. Department of Health and Human Services
National Institutes of HealthNational Human Genome Research
InstituteTeri A. Manolio, M.D., Ph.D.
Director, Office of Population Genomics andSenior Advisor to the Director, NHGRI,
for Population Genomics
![Page 2: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/2.jpg)
Topics to be Covered
• Discrete traits and quantitative traits
• Measures of association
• Detecting/correcting for false positives
• Genotyping quality control
• Quantile-quantile (Q-Q) plots
• Odds ratios: allelic and genotypic
• Models of genetic transmission
• Interactions: gene-gene, gene-environment
![Page 3: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/3.jpg)
Larson, G. The Complete Far Side. 2003.
![Page 4: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/4.jpg)
Quantitative Genetics
“…concerned with the inheritance of those differences between individuals that are of degree rather than of kind…”
Quantitative Qualitative
Falconer and Mackay, Quantitative Genetics 1996.
![Page 5: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/5.jpg)
Quantitative Genetics
“…concerned with the inheritance of those differences between individuals that are of degree rather than of kind…”
Quantitative Qualitative
Continuous gradation among individuals from one extreme to other
Sharply demarcated types with little connection by intermediates
Falconer and Mackay, Quantitative Genetics 1996.
![Page 6: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/6.jpg)
Quantitative Genetics
“…concerned with the inheritance of those differences between individuals that are of degree rather than of kind…”
Quantitative Qualitative
Continuous gradation among individuals from one extreme to other
Sharply demarcated types with little connection by intermediates
Effects of genes are small
Effects of genes are large
Falconer and Mackay, Quantitative Genetics 1996.
![Page 7: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/7.jpg)
Quantitative Genetics
“…concerned with the inheritance of those differences between individuals that are of degree rather than of kind…”
Quantitative Qualitative
Continuous gradation among individuals from one extreme to other
Sharply demarcated types with little connection by intermediates
Effects of genes are small
Effects of genes are large
Usually many genes Single genes inherited in Mendelian ratios?
Falconer and Mackay, Quantitative Genetics 1996.
![Page 8: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/8.jpg)
Inheritance Models in Single Gene Trait
A
a
![Page 9: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/9.jpg)
Genotype Group
Model AA Aa aa
Inheritance Models in Single Gene Trait
![Page 10: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/10.jpg)
Genotype Group
Model AA Aa aa
A is Dominant
Inheritance Models in Single Gene Trait
![Page 11: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/11.jpg)
Genotype Group
Model AA Aa aa
A is Dominant
Inheritance Models in Single Gene Trait
![Page 12: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/12.jpg)
Genotype Group
Model AA Aa aa
A is Dominant
A is Recessive
Inheritance Models in Single Gene Trait
![Page 13: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/13.jpg)
Genotype Group
Model AA Aa aa
A is Dominant
A is Recessive
A is Co-Dominant
Inheritance Models in Single Gene Trait
![Page 14: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/14.jpg)
Inheritance Models in Quantitative Trait
A x increase in height
a x decrease in height
![Page 15: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/15.jpg)
Population Mean
Model -x 0 +x
Inheritance Models in Quantitative Trait
![Page 16: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/16.jpg)
Population Mean
Model -x 0 +x
A is Completely Dominant
aa
AAAa
Inheritance Models in Quantitative Trait
![Page 17: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/17.jpg)
Population Mean
Model -x 0 +x
A is Completely Dominant
aa
AAAa
A is Partially Dominant
aa Aa AA
Inheritance Models in Quantitative Trait
![Page 18: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/18.jpg)
Population Mean
Model -x 0 +x
A is Completely Dominant
aa
AAAa
A is Partially Dominant
aa Aa AA
A is Not (Co-) Dominant
aa Aa AA
Inheritance Models in Quantitative Trait
![Page 19: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/19.jpg)
Population Mean
Model -x 0 +x
A is Completely Dominant
aa
AAAa
A is Partially Dominant
aa Aa AA
A is Not (Co-) Dominant
aa Aa AA
A is Over-Dominant
aa AA Aa
Inheritance Models in Quantitative Trait
![Page 20: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/20.jpg)
Quantitative Traits with Published GWA Studies (16 - 34)
•QT interval •Lipids and lipoproteins
•Memory•Nicotine dependence
•ORMDL3 expression•YKL-40 levels •Obesity, BMI, waist•Insulin resistance•Height
•Bone mineral density•F-cell distribution•Fetal hemoglobin levels
•C-Reactive protein•18 groups of Framingham traits
•Pigmentation•Uric Acid Levels•Recombination Rate
![Page 21: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/21.jpg)
Association of Alleles and Genotypes of rs1333049 (‘3049) with Myocardial
Infarction C
N (%)G
N (%)2
(1df)P-value
Cases2,132 (55.4)
1,716 (44.6)
55.11.2 x 10-
13Controls
2,783 (47.4)
3,089 (52.6)
Allelic Odds Ratio = 1.38
Samani N et al, N Engl J Med 2007; 357:443-453.
![Page 22: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/22.jpg)
Association of Alleles and Genotypes of rs1333049 (‘3049) with Myocardial
Infarction C
N (%)G
N (%)2
(1df)P-value
Cases2,132 (55.4)
1,716 (44.6)
55.11.2 x 10-
13Controls
2,783 (47.4)
3,089 (52.6)
Allelic Odds Ratio = 1.38CC
N (%)CG
N (%)GG
N (%)2
(2df) P-value
Cases586
(30.5) 960 (49.9)
378 (19.6)59.7
1.1 x 10-
14Controls
676 (23.0)
1,431 (48.7)
829 (28.2)
Heterozygote Odds Ratio = 1.47
Homozygote Odds Ratio = 1.90
Samani N et al, N Engl J Med 2007; 357:443-453.
![Page 23: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/23.jpg)
-Log10 P Values for SNP Associations with Myocardial
Infarction
Samani N et al, N Engl J Med 2007; 357:443-453.
![Page 24: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/24.jpg)
http://www.broad.mit.edu/diabetes/scandinavs/type2.html
Genome-Wide Scan for Type 2 Diabetes in a Scandinavian Cohort
![Page 25: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/25.jpg)
• Linear regression of inverse normalized levels against number of alleles
• Additive model• Sex, age, age2 as covariates
GWA Study of Serum Uric Acid Levels
Li S et al, PLoS Genet 2007; 3:e194.
![Page 26: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/26.jpg)
Association of rs6855911 and Uric Acid Levels
Li S et al, PLoS Genet 2007; 3:e194.
Genotype Means (mg/dl)
Cohort Additive Effect
AA AG GG
SardiNIA -0.317 4.66 (1.51)
4.48 (1.59)
4.02 (1.63)
InCHIANTI
-0.397 5.27 (1.44)
4.94 (1.31)
4.33 (1.37)
![Page 27: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/27.jpg)
Association Methods for Quantitative Traits
• Linear regression of multivariable adjusted residual against number of alleles (Kathiresan,Nat Genet 2008; 40:189-97)
• Linear regression of log transformed or centralized BMI against genotype (Frayling, Science 2007; 316:889-94)
• Variance components based Z-score analysis of quantile normalized height (Sanna, Nat Genet 2008; 40:198-203)
![Page 28: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/28.jpg)
Ways of Dealing with Multiple Testing
• Control family wise error rate (FWER): Bonferroni (α’ = α/n) or Sĭdák (α’ = 1- [1- α]1/n)
• False discovery rate: proportion of significant associations that are actually false positives
• False positive report probability: probability that the null hypothesis is true, given a statistically significant finding
• Bayes factors analysis: avoids need for assessing genome-wide error rates but must identify reasonable alternative model
Hogart CJ et al, Genet Epidemiol 2008; 32:179-85.
![Page 29: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/29.jpg)
Larson, G. The Complete Far Side. 2003.
![Page 30: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/30.jpg)
Quality Control of SNP Genotyping: Samples
• Identity with forensic markers (Identifiler)
• Blind duplicates
• Gender checks
• Cryptic relatedness or unsuspected twinning
• Degradation/fragmentation
• Call rate (> 80-90%)
• Heterozygosity: outliers
• Plate/batch calling effects
Chanock et al, Nature 2007; Manolio et al Nat Genet 2007
![Page 31: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/31.jpg)
Quality Control of SNP Genotyping: SNPs
• Duplicate concordance (CEPH samples)
• Mendelian errors (typically < 1)
• Hardy-Weinberg errors (often > 10-5)
• Heterozygosity (outliers)
• Call rate (typically > 98%)
• Minor allele frequency (often > 1%)
• Validation of most critical results on independent genotyping platform
Chanock et al, Nature 2007; Manolio et al Nat Genet 2007
![Page 32: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/32.jpg)
Hardy-Weinberg Equilibrium
• Occurrence of two alleles of a SNP in the same individual are two independent events
• Ideal conditions:– random mating - no selection (equal
survival)– no migration - no mutation– no inbreeding - large population sizes– gene frequencies equal in males and females)…
• If alleles A and a of SNP rs1234 have frequencies p and 1-p, expected frequencies of the three genotypes are:
After G. Thomas, NCI
Freq AA = p2 Freq Aa = 2p(1-p) Freq aa = (1-p)2
![Page 33: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/33.jpg)
Metric Perlegen Affymetrix/Broad
Number of SNPs 480,744 439,249
Coverage Single Marker
Multi-Marker
Single Marker
Multi-Marker
CEU 0.90 0.96 0.78 0.87 CHB + JPT 0.87 0.93 0.78 0.86 YRI 0.64 0.78 0.63 0.75Average call rate 98.9% 99.3%
Concordance
Homozygous genotypes 99.8% 99.9%
Heterozygous genotypes 99.8% 99.8%
Coverage, Call Rates, and Concordance of Perlegen and Affymetrix Platforms on
HapMap Phase II
GAIN Collaborative Group, Nat Genet 2007; 39:1045-51.
![Page 34: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/34.jpg)
Metric 5.0 % fail 6.0 % failTotal Samples 1,829 -- 2,289 --Passing QC 1,817 0.44 2,192 4.24> 98% call rate 1,815 0.55 2,257 1.40
Sample and SNP QC Metrics for Affymetrix 5.0 and 6.0 Platforms in GAIN
Courtesy, J Paschall, NCBI
![Page 35: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/35.jpg)
Metric 5.0 % fail 6.0 % failTotal Samples 1,829 -- 2,289 --Passing QC 1,817 0.44 2,192 4.24> 98% call rate 1,815 0.55 2,257 1.40
Total SNPs 457,645 -- 906,660 --Passing QC 429,309 6.19 845,814 6.70MAF > 1% 457,466 0.04 888,234 2.03> 98% call rate 419,810 8.27 821,942 9.34> 95% call rate 439,272 4.01 873,856 3.61HWE < 10 -6 455,899 0.38 904,275 0.26< 1 Mendel error 417,722 8.72 899,721 0.01
< 1 Duplicate error 454,820 0.01 892,103 0.02
Sample and SNP QC Metrics for Affymetrix 5.0 and 6.0 Platforms in GAIN
Courtesy, J Paschall, NCBI
![Page 36: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/36.jpg)
Sample Heterozygosity in GAIN
0
500
1,000
1,500
2,000
2,500
0.20 0.22 0.24 0.26 0.28 0.30 0.32 0.34 0.36 0.38 0.40
Fre
quency
Courtesy, J Paschall, NCBI
![Page 37: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/37.jpg)
Sample Heterozygosity in GAIN
0
10
20
30
40
50
60
70
80
90
100
0.20 0.22 0.24 0.26 0.28 0.30 0.32 0.34 0.36 0.38 0.40
Fre
quency
Courtesy, J Paschall, NCBI
![Page 38: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/38.jpg)
Signal Intensity Plots for rs10801532 in AREDS
http://www.ncbi.nlm.nih.gov/sites/entrez
![Page 39: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/39.jpg)
Signal Intensity Plots for rs4639796 in AREDS
http://www.ncbi.nlm.nih.gov/sites/entrez
![Page 40: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/40.jpg)
Signal Intensity Plots for rs534399 in AREDS
http://www.ncbi.nlm.nih.gov/sites/entrez
![Page 41: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/41.jpg)
Signal Intensity Plots for rs572515 in AREDS
http://www.ncbi.nlm.nih.gov/sites/entrez
![Page 42: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/42.jpg)
Signal Intensity Plots for CD44 SNP rs9666607
Clayton DG et al, Nat Genet 2005; 37:1243-1246.
![Page 43: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/43.jpg)
Courtesy, G. Thomas, NCI
Principal Component Analysis of Structured Population: First to Third
Components
![Page 44: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/44.jpg)
Courtesy, G. Thomas, NCI
Principal Component Analysis of Structured Population: Fourth and
Fifth Components
![Page 45: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/45.jpg)
Courtesy, G. Thomas, NCI
Influence of Relatedness on Principal Component Analysis
![Page 46: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/46.jpg)
Courtesy, G. Thomas, NCI
Principal Component Analysis of Structured Population: Fourth and
Fifth Components
![Page 47: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/47.jpg)
Courtesy, G. Thomas, NCI
Principal Component Analysis of Structured Population: Fourth and
Fifth Components
![Page 48: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/48.jpg)
Summary Points: Genotyping Quality Control
• Sample checks for identity, gender error, cryptic relatedness
• Sample handling differences can introduce artifacts but probably can be adjusted for
• Association analysis is often quickest way to find genotyping errors
• Low MAF SNPs are most difficult to call
• Inspection of genotyping cluster plots is crucial!
![Page 49: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/49.jpg)
Easton D et al, Nature 2007; 447:1087-1093.
Quantile-Quantile Plot for Test Statistics,
390 Breast Cancer Cases, 364 Controls
205,586 SNPsλ = 1.03
![Page 50: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/50.jpg)
Easton D et al, Nature 2007; 447:1087-93.
Observed and Expected Associations after Stage 2 of Breast
Cancer GWASignificance
Observed
Observed
Adjusted
Expected
Ratio
0.01 - 0.05 1,239 1,162 934 1.24
10-3 – 10-2 574 517 348 1.49
10-4 – 10-3 112 88 53 1.65
10-5 – 10-4 16 12 7 1.71
< 10-5 15 13 1 13.5
All p < 0.05 1,956 1,792 1,343 1.33
![Page 51: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/51.jpg)
Q-Q Plot for Multiple Sclerosis; Effect of MHC
Hafler D et al, N Engl J Med 2007; 357:851-862.
![Page 52: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/52.jpg)
Q-Q Plot for Prostate Cancer, all SNPs
Gudmundsson J et al, Nat Genet 2007; 39:977-983.
![Page 53: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/53.jpg)
Q-Q Plot for Prostate Cancer, excluding Chromosome 8
Gudmundsson J et al, Nat Genet 2007; 39:977-983.
![Page 54: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/54.jpg)
Q-Q Plot for Myocardial Infarction
Samani N et al, N Engl J Med 2007; 357:443-453.
Expected chi-squared statistic0 5 10 15 20 25
Obs
erve
d ch
i-squ
ared
sta
tistic
0
2
0
40
60
![Page 55: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/55.jpg)
-Log10 P Values for SNP Associations with Myocardial
Infarction
Samani N et al, N Engl J Med 2007; 357:443-453.
![Page 56: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/56.jpg)
-Log10 P Values for SNP Associations with Myocardial
Infarction
Samani N et al, N Engl J Med 2007; 357:443-453.
![Page 57: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/57.jpg)
SNP Associations with 1,928 MI Cases and 2,938 Controls from UK
Samani N et al, N Engl J Med 2007; 357:443-453.
![Page 58: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/58.jpg)
Association Signal for Coronary Artery Disease on Chromosome 9
’3049
Samani N et al, N Engl J Med 2007; 357:443-453.
![Page 59: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/59.jpg)
Winner’s Curse: Odds Ratios for CHD Associated with LTA Genotypes in
Multiple Studies
Clarke et al, PLoS Genet 2006; 2:e107.
![Page 60: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/60.jpg)
Genome-Wide Scan for Alzheimer’s Disease in 861 Cases and 550
Controls
Reiman E et al, Neuron 2007; 54:713-20.
![Page 61: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/61.jpg)
Genome-Wide Scan for Alzheimer’s Disease in ApoE*e4Carriers
Reiman E et al, Neuron 2007; 54:713-20.
![Page 62: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/62.jpg)
LOAD Odds Ratios Associated with rs2373115 GG by APOE*e4 Status
APOE*e4 Group
APOE*e4 OR [95% CI]
rs2373115OR [95%CI]
APOE*e4 - 1.12 [0.82,1.53]
APOE*e4 + 2.88 [1.90,4.36]
All6.07 [4.63-
7.95]1.34 [1.06,1.70]
Reiman et al, Neuron 2007; 54:713-720.
![Page 63: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/63.jpg)
Klein et al, Science 2005; 308:385-389.
P Values of GWA Scan for Age-Related Macular Degeneration
![Page 64: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/64.jpg)
Klein et al, Science 2005; 308:385-389.
Odds Ratios and Population Attributable Risks for AMD
Attribute (SNP) rs380390
(C/G) rs1329428
(C/T)
Risk allele C C
Allelic association χ2 P value 4.1 x 10–8 1.4 x 10–6
Odds ratio (dominant) 4.6 [2.0-11] 4.7 [1.0-22]
Frequency in HapMap CEU 0.70 0.82
Population Attributable Risk
70% [42-84%] 80% [0-96%]
Odds ratio (recessive) 7.4 [2.9-19] 6.2 [2.9-13]
Frequency in HapMap CEU 0.23 0.41
Population Attributable Risk
46% [31-57%]
61% [43-73%]
![Page 65: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/65.jpg)
Risk of Developing AMD by CFH Y402H and Modifiable Risk Factors
Schaumberg DA et al, Arch Ophthalmol 2007; 125:55-62.
Risk Factor
CFH Y402H Genotype
YY YH HH
BMI < 30 kg/m2 1.00 1.95
[1.42-2.67]3.96
[2.69-5.82]
BMI > 30 kg/m2
1.98 [0.91-4.31]
2.19 [1.11-4.30]
12.28 [4.88-30.90]
Non-smoker 1.00 1.95 [1.41-2.71]
4.23 [2.86-6.27]
Current smoker
2.34 [1.20-4.55]
3.20 [1.85-5.55]
8.69 [3.86-19.57]
![Page 66: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/66.jpg)
TT
CC
CT
Ordovas et al, Circulation 2002; 106:2315-2321.
Interaction: Is LIPC Genotype Related to HDL-C?
TT CC
CT
![Page 67: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/67.jpg)
Inverse Relation between Endotoxin Exposure and Allergic Sensitization
by CD14 Genotype
Simpson A et al, Am J Respir Crit Care Med 2006;174:386-392.
![Page 68: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/68.jpg)
Challenges in Studying Gene-Environment Interactions
Challenge GenesEnvironme
nt
Ease of measure Pretty easy Often hard
Variability over time
Low/none High
Recall bias None Possible
Temporal relation to disease
Easy Hard
![Page 69: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/69.jpg)
Larson, G. The Complete Far Side. 2003.
![Page 70: Genetics for Epidemiologists Lecture 5: Analysis of Genetic Association Studies](https://reader036.fdocuments.in/reader036/viewer/2022062500/56815a63550346895dc7a783/html5/thumbnails/70.jpg)