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

Nature Genetics volume 50, pages 1311–1317 (2018)Cite this article

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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.

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Fig. 1: ASMC accuracy in coalescent simulations.
Fig. 2: Running time of ASMC.
Fig. 3: Genome-wide scan for recent positive selection in the UK Biobank dataset.
Fig. 4: S-LDSC analysis of ASMCavg background selection annotation and disease heritability.

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Acknowledgements

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.

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Authors and Affiliations

  1. Department of Statistics, University of Oxford, Oxford, UK

    Pier Francesco Palamara

  2. Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA

    Pier Francesco Palamara & Alkes L. Price

  3. Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA

    Pier Francesco Palamara & Alkes L. Price

  4. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Pier Francesco Palamara & Alkes L. Price

  5. Department of Statistics, University of Michigan, Ann Arbor, MI, USA

    Jonathan Terhorst

  6. Department of Statistics, University of California, Berkeley, Berkeley, CA, USA

    Yun S. Song

  7. Computer Science Division, University of California, Berkeley, Berkeley, CA, USA

    Yun S. Song

  8. Chan Zuckerberg Biohub, San Francisco, CA, USA

    Yun S. Song

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  1. Pier Francesco Palamara
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  2. Jonathan Terhorst
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Contributions

P.F.P. and A.L.P. conceived the study and analyzed results. P.F.P. developed the ASMC algorithm, performed simulations and data analysis. J.T. and Y.S.S. developed the CSFS model used in the SMC++ and ASMC algorithms. P.F.P. and A.L.P. wrote the manuscript with comments from J.T. and Y.S.S.

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Correspondence to Pier Francesco Palamara or Alkes L. Price.

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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

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