Genetic loci associated with coronary artery disease harbor evidence of selection and antagonistic pleiotropy
The 40 of 76 CAD genes investigated are shown that have at least four significant selection-risk associations in Panel B across all 12 populations. Panel A. Magnitude and significance of largest positive selection signal (integrated haplotype score, iHS) within each gene-population combination. P values (circles within squares) were obtained from 10000 permutations. Bonferroni corrected p value limit also shown (α = 0.05/76 = 0.000657) with closed circles. Panel B. Null hypothesis: no association between CAD genetic risk and positive selection, tested using mixed effects model with SNP estimates of CAD log odds genetic risk and iHS while accounting for gene LD structure as a random effect (first eigenvector from LD matrix per gene). Scaled regression coefficients were obtained directly from regressions, each p value from 10000 permutations. Panel C. Null hypothesis: association between genetic risk and positive selection for SNPs within CAD genes no different than non-CAD associated genes. Permuted p values were estimated by comparing each p value in Panel B against 100 nominal p values obtained by randomly choosing (without replacement) 100 non-CAD associated genes of similar size across the genome and using the same mixed effects model setup as described above. Populations. Grouped by ancestry, African (ASW, African ancestry in Southwest USA; MKK, Maasai in Kinyawa, Kenya; YRI, Yoruba from Ibadan, Nigeria; LWK, Luhya in Webuye, Kenya), East-Asian (CHB, Han Chinese subjects from Beijing; CHD, Chinese in Metropolitan Denver, Colorado; JPT, Japanese subjects from Tokyo), European (CEU, Utah residents with ancestry from northern and western Europe from the CEPH collection; TSI, Tuscans in Italy; FIN, Finnish in Finland), GIH (Gujarati Indians in Houston, TX, USA), MEX (Mexican ancestry in Los Angeles, CA, USA).