Distribution of allele frequencies and effect sizes and their interrelationships for common genetic susceptibility variants

Abstract

Recent discoveries of hundreds of common susceptibility SNPs from genome-wide association studies provide a unique opportunity to examine population genetic models for complex traits. In this report, we investigate distributions of various population genetic parameters and their interrelationships using estimates of allele frequencies and effect-size parameters for about 400 susceptibility SNPs across a spectrum of qualitative and quantitative traits. We calibrate our analysis by statistical power for detection of SNPs to account for overrepresentation of variants with larger effect sizes in currently known SNPs that are expected due to statistical power for discovery. Across all qualitative disease traits, minor alleles conferred "risk" more often than "protection." Across all traits, an inverse relationship existed between "regression effects" and allele frequencies. Both of these trends were remarkably strong for type I diabetes, a trait that is most likely to be influenced by selection, but were modest for other traits such as human height or late-onset diseases such as type II diabetes and cancers. Across all traits, the estimated effect-size distribution suggested the existence of increasingly large numbers of susceptibility SNPs with decreasingly small effects. For most traits, the set of SNPs with intermediate minor allele frequencies (5-20%) contained an unusually small number of susceptibility loci and explained a relatively small fraction of heritability compared with what would be expected from the distribution of SNPs in the general population. These trends could have several implications for future studies of common and uncommon variants.

Fig. 1.

Distribution of frequencies for minor alleles across an estimated number of susceptibility SNPs (yellow), observed susceptibility SNPs (green), and independent representative SNPs in the HapMap project (blue).

Fig. 2.

Smoothed estimate of distribution of regression coefficients associated with minor alleles for susceptibility loci, shown with (red) and without power adjustment (blue). OR, odds ratio.

Fig. 3.

Scatter plots for the 2D distribution of regression effects and minor-allele frequencies for observed susceptibility SNPs. The analysis is performed in the scale of squared regression coefficients β² and f(1 − f), which are the components that define the contribution of a SNP to genetic variance. In the background of each plot, the power of the original discovery study is shown in gray scale over different regions of the parameter space. The weight for each SNP, which is the inverse of its power for detection, is proportional to the area of the purple circle surrounding it. Fitted lines with (red lines) and without weights (blue lines) are shown.