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; Kay Yan Benjamin 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 Bopp; Amarjit 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

doi:10.1038/ng.3595

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, Kay Yan Benjamin 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

Research output: Journal article publication › Journal article › Academic research › peer-review

99 Citations (Scopus)

Abstract

Two bottlenecks impeding the genetic analysis of complex traits in rodents are access to mapping populations able to deliver gene-level mapping resolution and the need for population-specific genotyping arrays and haplotype reference panels. Here we combine low-coverage (0.15×) sequencing with a new method to impute the ancestral haplotype space in 1,887 commercially available outbred mice. We mapped 156 unique quantitative trait loci for 92 phenotypes at a 5% false discovery rate. Gene-level mapping resolution was achieved at about one-fifth of the loci, implicating Unc13c and Pgc1a at loci for 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. These findings have implications for diverse areas of mammalian biology and demonstrate how genome-wide association studies can be extended via low-coverage sequencing to species with highly recombinant outbred populations.

Original language	English
Pages (from-to)	912-918
Number of pages	7
Journal	Nature Genetics
Volume	48
Issue number	8
DOIs	https://doi.org/10.1038/ng.3595
Publication status	Published - 1 Aug 2016

ASJC Scopus subject areas

Genetics

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10.1038/ng.3595

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Nicod, J., Davies, R. W., Cai, N., Hassett, C., Goodstadt, L., Cosgrove, C., Yee, K. Y. B., Lionikaite, V., McIntyre, R. E., Remme, C. A., Lodder, E. M., Gregory, J. S., Hough, T., Joynson, R., Phelps, H., Nell, B., Rowe, C., Wood, J., Walling, A., ... Flint, J. (2016). Genome-wide association of multiple complex traits in outbred mice by ultra-low-coverage sequencing. Nature Genetics, 48(8), 912-918. https://doi.org/10.1038/ng.3595

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

abstract = "Two bottlenecks impeding the genetic analysis of complex traits in rodents are access to mapping populations able to deliver gene-level mapping resolution and the need for population-specific genotyping arrays and haplotype reference panels. Here we combine low-coverage (0.15×) sequencing with a new method to impute the ancestral haplotype space in 1,887 commercially available outbred mice. We mapped 156 unique quantitative trait loci for 92 phenotypes at a 5% false discovery rate. Gene-level mapping resolution was achieved at about one-fifth of the loci, implicating Unc13c and Pgc1a at loci for 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. These findings have implications for diverse areas of mammalian biology and demonstrate how genome-wide association studies can be extended via low-coverage sequencing to species with highly recombinant outbred populations.",

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

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Nicod, J, Davies, RW, Cai, N, Hassett, C, Goodstadt, L, Cosgrove, C, Yee, KYB, Lionikaite, V, McIntyre, RE, Remme, CA, Lodder, EM, Gregory, JS, Hough, T, Joynson, R, Phelps, H, Nell, B, Rowe, C, Wood, J, Walling, A, Bopp, N, Bhomra, A, Hernandez-Pliego, P, Callebert, J, Aspden, RM, Talbot, NP, Robbins, PA, Harrison, M, Fray, M, Launay, JM, Pinto, YM, Blizard, DA, Bezzina, CR, Adams, DJ, Franken, P, Weaver, T, Wells, S, Brown, SDM, Potter, PK, Klenerman, P, Lionikas, A, Mott, R & Flint, J 2016, 'Genome-wide association of multiple complex traits in outbred mice by ultra-low-coverage sequencing', Nature Genetics, vol. 48, no. 8, pp. 912-918. https://doi.org/10.1038/ng.3595

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AU - Davies, Robert W.

AU - Cai, Na

AU - Hassett, Carl

AU - Goodstadt, Leo

AU - Cosgrove, Cormac

AU - Yee, Kay Yan Benjamin

AU - Lionikaite, Vikte

AU - McIntyre, Rebecca E.

AU - Remme, Carol Ann

AU - Lodder, Elisabeth M.

AU - Gregory, Jennifer S.

AU - Hough, Tertius

AU - Joynson, Russell

AU - Phelps, Hayley

AU - Nell, Barbara

AU - Rowe, Clare

AU - Wood, Joe

AU - Walling, Alison

AU - Bopp, Nasrin

AU - Bhomra, Amarjit

AU - Hernandez-Pliego, Polinka

AU - Callebert, Jacques

AU - Aspden, Richard M.

AU - Talbot, Nick P.

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AU - Harrison, Mark

AU - Fray, Martin

AU - Launay, Jean Marie

AU - Pinto, Yigal M.

AU - Blizard, David A.

AU - Bezzina, Connie R.

AU - Adams, David J.

AU - Franken, Paul

AU - Weaver, Tom

AU - Wells, Sara

AU - Brown, Steve D.M.

AU - Potter, Paul K.

AU - Klenerman, Paul

AU - Lionikas, Arimantas

AU - Mott, Richard

AU - Flint, Jonathan

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

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