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.
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Identity-by-descent detection across 487,409 British samples reveals fine scale population structure and ultra-rare variant associations
Nature Communications Open Access 30 November 2020
European Journal of Human Genetics Open Access 25 July 2020
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We thank P.-R. Loh for suggesting several coding improvements for the ASMC software, and for support with the phasing and processing of the UK Biobank data; S. Gazal for support with the S-LDSC analysis and the baselineLD model; I. Shlyakhter for support with the COSI2 simulator; Y. Field for support with the simulation setup in the analysis of recent positive selection; D. Reich for providing computational resources; H. Finucane, Y. Reshef and S. Gusev for helpful discussions. This research was conducted using publicly available datasets (see URLs): the UK Biobank Resource under Application #16549, and the Genome of the Netherlands resource under Application #2017149. We thank the participants of the UK Biobank and the Genome of the Netherlands projects. P.F.P. and A.L.P. were supported by NIH grants R01 MH101244, R01 HG006399 and R01 GM105857; J.T. and Y.S.S. were supported in part by NIH grant R01 GM094402 and a Packard Fellowship for Science and Engineering; Y.S.S. is a Chan Zuckerberg Biohub investigator.
The authors declare no competing interests.
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Palamara, P.F., Terhorst, J., Song, Y.S. et al. High-throughput inference of pairwise coalescence times identifies signals of selection and enriched disease heritability. Nat Genet 50, 1311–1317 (2018). https://doi.org/10.1038/s41588-018-0177-x
Nature Human Behaviour (2021)
Identity-by-descent detection across 487,409 British samples reveals fine scale population structure and ultra-rare variant associations
Nature Communications (2020)
Human Genetics (2020)
European Journal of Human Genetics (2020)