Genome-wide association of multiple complex traits in outbred mice by ultra low-coverage sequencing

Jérôme Nicod, Robert W. Davies, Na Cai, Carl Hassett, Leo Goodstadt, Cormac Cosgrove, Benjamin K. Yee, Vikte Lionikaite, Rebecca E. McIntyre, Carol Ann Remme, Elisabeth M. Lodder, Jennifer S. Gregory, Tertius Hough, Russell Joynson, Hayley Phelps, Barbara Nell, Clare Rowe, Joe Wood, Alison Walling, Nasrin BoppAmarjit Bhomra, Polinka Hernandez-Pliego, Jacques Callebert, Richard M. Aspden, Nick P. Talbot, Peter A. Robbins, Mark Harrison, Martin Fray, Jean-Marie Launay, Yigal M. Pinto, David A. Blizard, Connie R. Bezzina, David J. Adams, Paul Franken, Tom Weaver, Sara Wells, Steve D. M. Brown, Paul K. Potter, Paul Klenerman, Arimantas Lionikas, Richard Mott, Jonathan Flint

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Two bottlenecks that have impeded the genetic analysis of complex traits in inbred strain crosses and populations derived from them, are the lack of gene level mapping resolution and the need for population specific genotyping arrays and haplotype reference panels. To address these problems we mapped multiple complex traits at high resolution in a highly recombinant commercially-available outbred mouse population, using imputed genotypes from 0.15x whole genome sequencing. By simultaneously imputing the ancestral haplotype space comprising 5,766,828 single nucleotide polymorphisms and the genomes of the mapping population at 359,559 tagging variants, we mapped 255 quantitative trait loci representing 156 unique regions in 1,887 mice for 92 phenotypes. Linkage disequilibrium decays fast enough to provide gene-level mapping resolution at about a fifth of loci. Our results implicate Unc13c and Pgc1-alpha at loci affecting the quality of sleep, Adarb2 for home cage activity, Rtkn2 for intensity of reaction to startle, Bmp2 for wound healing, Il15 and Id2 for several T-cell measures and Prkca for bone mineral content. Six diverse phenotypes map over the Met gene: muscle weight, startle response, serum albumin, calcium, protein and cholesterol levels, suggesting this is an important pleiotropic locus. These findings have implications for diverse areas of mammalian biology and demonstrate how GWAS can be extended via low-coverage sequencing to species with large highly recombinant outbred populations.
Original languageEnglish
Pages (from-to)912-918
Number of pages7
JournalNature Genetics
Issue number8
Early online date4 Jul 2016
Publication statusPublished - 31 Aug 2016

Bibliographical note

The authors wish to acknowledge excellent technical assistance from A. Kurioka, L. Swadling, C. de Lara, J. Ussher, R. Townsend, S. Lionikaite, A.S. Lionikiene, R. Wolswinkel and I. van der Made. We would like to thank T.M. Keane and A.G. Doran for their help in annotating variants and adding the FVB/NJ strain to the MGP. We thank the High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics and the Wellcome Trust Sanger Institute for the generation of the sequencing data. This work was funded by Wellcome Trust grant 090532/Z/09/Z (J.F.). Primary phenotyping of the mice was supported by the Mary Lyon Centre and Mammalian Genetics Unit (Medical Research Council, UK Hub grant G0900747 91070 and Medical Research Council, UK grant MC U142684172). D.A.B. acknowledges support from NIH R01AR056280. The sleep work was supported by the state of Vaud (Switzerland) and the Swiss National Science Foundation (SNF 14694 and 136201 to P.F.). The ECG work was supported by the Netherlands CardioVascular Research Initiative (Dutch Heart Foundation, Dutch Federation of University Medical Centres, Netherlands Organization for Health Research and Development and the Royal Netherlands Academy of Sciences) PREDICT project, InterUniversity Cardiology Institute of the Netherlands (ICIN; 061.02; C.A.R. and C.R.B.). N.C. is supported by the Agency of Science, Technology and Research (A*STAR) Graduate Academy. R.W.D. is supported by a grant from the Wellcome Trust (097308/Z/11/Z).


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