High-throughput inference of pairwise coalescence times identifies signals of selection and enriched disease heritability.
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Abstract | Interest in reconstructing demographic histories has motivated the development of methods to estimate locus-specific pairwise coalescence times from whole-genome sequencing data. Here we introduce a powerful new method, ASMC, that can estimate coalescence times using only SNP array data, and is orders of magnitude faster than previous approaches. We applied ASMC to detect recent positive selection in 113,851 phased British samples from the UK Biobank, and detected 12 genome-wide significant signals, including 6 novel loci. We also applied ASMC to sequencing data from 498 Dutch individuals to detect background selection at deeper time scales. We detected strong heritability enrichment in regions of high background selection in an analysis of 20 independent diseases and complex traits using stratified linkage disequilibrium score regression, conditioned on a broad set of functional annotations (including other background selection annotations). These results underscore the widespread effects of background selection on the genetic architecture of complex traits. |
Year of Publication | 2018
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Journal | Nat Genet
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Volume | 50
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Issue | 9
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Pages | 1311-1317
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Date Published | 2018 09
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ISSN | 1546-1718
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DOI | 10.1038/s41588-018-0177-x
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PubMed ID | 30104759
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PubMed Central ID | PMC6145075
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Grant list | MC_QA137853 / MRC_ / Medical Research Council / United Kingdom
R01 HG006399 / HG / NHGRI NIH HHS / United States
R03 ES027902 / ES / NIEHS NIH HHS / United States
R01 GM094402 / GM / NIGMS NIH HHS / United States
R01 GM105857 / GM / NIGMS NIH HHS / United States
U01 HG009379 / HG / NHGRI NIH HHS / United States
MC_PC_17228 / MRC_ / Medical Research Council / United Kingdom
R01 MH101244 / MH / NIMH NIH HHS / United States
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