Linkage Disequilibrium and Heterozygosity Modulate the Genetic Architecture of Human Complex Phenotypes: Evidence of Natural Selection from GWAS Summary Statistics

Dominic Holland, Oleksandr Frei, Rahul Desikan, Chun-Chieh Fan, Alexey A. Shadrin, Olav B. Smeland, Ole A. Andreassen, Anders M. Dale

Aug 16, 2019

Received Date: 9th August 19

We propose an extended Gaussian mixture model for the distribution ofcausal effects of common single nucleotide polymorphisms (SNPs) forhuman complex phenotypes, taking into account linkage disequilibrium(LD) and heterozygosity (H), while also allowing for independentcomponents for small and large effects. Using a precise methodologyshowing how genome-wide association studies (GWAS) summary statistics(z-scores) arise through LD with underlying causal SNPs, we appliedthe model to multiple GWAS. Our findings indicated that causal effectsare distributed with dependence on a SNP's total LD and H, wherebySNPs with lower total LD are more likely to be causal, and causal SNPswith lower H tend to have larger effects, consistent with theinfluence of negative pressure from natural selection. The degree ofdependence, however, varies markedly across phenotypes.

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