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Linkage Disequilibrium and Heterozygosity Modulate the Genetic Architecture of Human Complex Phenotypes

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

Posted 16 Jul 2019
bioRxiv DOI: 10.1101/705285

We propose an extended Gaussian mixture model for the distribution of causal effects of common single nucleotide polymorphisms (SNPs) for human complex phenotypes that depends on linkage disequilibrium (LD) and heterozygosity (H), while also allowing for independent components for small and large effects. Using a precise methodology showing how genome-wide association studies (GWAS) summary statistics (z-scores) arise through LD with underlying causal SNPs, we applied the model to GWAS of multiple human phenotypes. Our findings indicated that causal effects are distributed with dependence on total LD and H, whereby SNPs with lower total LD and H are more likely to be causal with larger effects; this dependence is consistent with models of the influence of negative pressure from natural selection. Compared with the basic Gaussian mixture model it is built on, the extended model -- primarily through quantification of selection pressure -- reproduces with greater accuracy the empirical distributions of z-scores, thus providing better estimates of genetic quantities, such as polygenicity and heritability, that arise from the distribution of causal effects. ### Competing Interest Statement Dr. Andreassen has received speaker's honorarium from Lundbeck, and is a consultant to HealthLytix. Dr. Dale is a Founder of and holds equity in CorTechs Labs, Inc, and serves on its Scientific Advisory Board. He is a member of the Scientific Advisory Board of Human Longevity, Inc. and receives funding through research agreements with General Electric Healthcare and Medtronic, Inc. The terms of these arrangements have been reviewed and approved by UCSD in accordance with its conflict of interest policies. The other authors declare no competing interests.

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