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High-throughput inference of pairwise coalescence times identifies signals of selection and enriched disease heritability

By Pier Francesco Palamara, Jonathan Terhorst, Yun S. Song, Alkes Price

Posted 07 Mar 2018
bioRxiv DOI: 10.1101/276931 (published DOI: 10.1038/s41588-018-0177-x)

Interest in reconstructing demographic histories has motivated the development of methods to estimate locus-specific pairwise coalescence times from whole-genome sequence data. We developed a new method, ASMC, that can estimate coalescence times using only SNP array data, and is 2-4 orders of magnitude faster than previous methods when sequencing data are available. We were thus able to apply ASMC to 113,851 phased British samples from the UK Biobank, aiming to detect recent positive selection by identifying loci with unusually high density of very recent coalescence times. We detected 12 genome-wide significant signals, including 6 loci with previous evidence of positive selection and 6 novel loci, consistent with coalescent simulations showing that our approach is well-powered to detect recent positive selection. We also applied ASMC to sequencing data from 498 Dutch individuals (Genome of the Netherlands data set) to detect background selection at deeper time scales. We observed highly significant correlations between average coalescence time inferred by ASMC and other measures of background selection. We investigated whether this signal translated into an enrichment in disease and complex trait heritability by analyzing summary association statistics from 20 independent diseases and complex traits (average N=86k) using stratified LD score regression. Our background selection annotation based on average coalescence time was strongly enriched for heritability (p = 7×10-153) in a joint analysis conditioned on a broad set of functional annotations (including other background selection annotations), meta-analyzed across traits; SNPs in the top 20% of our annotation were 3.8x enriched for heritability compared to the bottom 20%. These results underscore the widespread effects of background selection on disease and complex trait heritability.

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