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
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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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.