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  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, 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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Abstract

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 language	English
Pages (from-to)	912-918
Number of pages	7
Journal	Nature Genetics
Volume	48
Issue number	8
Early online date	4 Jul 2016
DOIs	https://doi.org/10.1038/ng.3595
Publication status	Published - 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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Richard Aspden
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Jenny Gregory
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Arimantas Lionikas
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Nicod, J., Davies, R. W., Cai, N., Hassett, C., Goodstadt, L., Cosgrove, C., Yee, B. K., 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

Nicod, J, Davies, RW, Cai, N, Hassett, C, Goodstadt, L, Cosgrove, C, Yee, BK, 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, J-M, 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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title = "Genome-wide association of multiple complex traits in outbred mice by ultra low-coverage sequencing",

abstract = "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.",

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, {Benjamin K.} 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 Jean-Marie Launay 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",

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).",

year = "2016",

month = aug,

day = "31",

doi = "10.1038/ng.3595",

language = "English",

volume = "48",

pages = "912--918",

journal = "Nature Genetics",

issn = "1061-4036",

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T1 - Genome-wide association of multiple complex traits in outbred mice by ultra low-coverage sequencing

AU - Nicod, Jérôme

AU - Davies, Robert W.

AU - Cai, Na

AU - Hassett, Carl

AU - Goodstadt, Leo

AU - Cosgrove, Cormac

AU - Yee, Benjamin K.

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.

AU - Robbins, Peter A.

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

N1 - 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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Y1 - 2016/8/31

N2 - 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.

AB - 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.

U2 - 10.1038/ng.3595

DO - 10.1038/ng.3595

M3 - Article

SN - 1061-4036

VL - 48

SP - 912

EP - 918

JO - Nature Genetics

JF - Nature Genetics

IS - 8

ER -

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

Abstract

Bibliographical note

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