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.
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford, UK.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Nicod
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford, UK.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Davies
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford, UK.
authors.forename: Na
authors.identifier: 0000-0001-7496-2075
authors.initials: N
authors.lastname: Cai
authors.affiliation: Mary Lyon Centre, MRC Harwell, Harwell Science and Innovation Campus, Harwell, UK.
authors.forename: Carl
authors.initials: C
authors.lastname: Hassett
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford, UK.
authors.forename: Leo
authors.initials: L
authors.lastname: Goodstadt
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Cormac
authors.initials: C
authors.lastname: Cosgrove
authors.affiliation: Department of Rehabilitation Sciences, Hong Kong Polytechnic University, Hong Kong, China.
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Yee
authors.affiliation: School of Medicine, Medical Sciences and Nutrition, College of Life Sciences and Medicine, University of Aberdeen, Aberdeen, UK.
authors.forename: Vikte
authors.initials: V
authors.lastname: Lionikaite
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: McIntyre
authors.affiliation: Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Carol Ann
authors.initials: CA
authors.lastname: Remme
authors.affiliation: Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Elisabeth M
authors.identifier: 0000-0001-6017-3796
authors.initials: EM
authors.lastname: Lodder
authors.affiliation: School of Medicine, Medical Sciences and Nutrition, College of Life Sciences and Medicine, University of Aberdeen, Aberdeen, UK.
authors.forename: Jennifer S
authors.identifier: 0000-0002-6328-4560
authors.initials: JS
authors.lastname: Gregory
authors.affiliation: Mary Lyon Centre, MRC Harwell, Harwell Science and Innovation Campus, Harwell, UK.
authors.forename: Tertius
authors.initials: T
authors.lastname: Hough
authors.affiliation: Mary Lyon Centre, MRC Harwell, Harwell Science and Innovation Campus, Harwell, UK.
authors.forename: Russell
authors.initials: R
authors.lastname: Joynson
authors.affiliation: Mary Lyon Centre, MRC Harwell, Harwell Science and Innovation Campus, Harwell, UK.
authors.forename: Hayley
authors.initials: H
authors.lastname: Phelps
authors.affiliation: Mary Lyon Centre, MRC Harwell, Harwell Science and Innovation Campus, Harwell, UK.
authors.forename: Barbara
authors.initials: B
authors.lastname: Nell
authors.affiliation: Mary Lyon Centre, MRC Harwell, Harwell Science and Innovation Campus, Harwell, UK.
authors.forename: Clare
authors.initials: C
authors.lastname: Rowe
authors.affiliation: Mary Lyon Centre, MRC Harwell, Harwell Science and Innovation Campus, Harwell, UK.
authors.forename: Joe
authors.initials: J
authors.lastname: Wood
authors.affiliation: Mary Lyon Centre, MRC Harwell, Harwell Science and Innovation Campus, Harwell, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Walling
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford, UK.
authors.forename: Nasrin
authors.initials: N
authors.lastname: Bopp
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford, UK.
authors.forename: Amarjit
authors.initials: A
authors.lastname: Bhomra
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford, UK.
authors.forename: Polinka
authors.initials: P
authors.lastname: Hernandez-Pliego
authors.affiliation: Department of Biochemistry, AP-HP, Hôpital Lariboisière, INSERM U942, Paris, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Callebert
authors.affiliation: School of Medicine, Medical Sciences and Nutrition, College of Life Sciences and Medicine, University of Aberdeen, Aberdeen, UK.
authors.forename: Richard M
authors.identifier: 0000-0002-0693-1194
authors.initials: RM
authors.lastname: Aspden
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Nick P
authors.initials: NP
authors.lastname: Talbot
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Robbins
authors.affiliation: Mary Lyon Centre, MRC Harwell, Harwell Science and Innovation Campus, Harwell, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Harrison
authors.affiliation: Mary Lyon Centre, MRC Harwell, Harwell Science and Innovation Campus, Harwell, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Fray
authors.affiliation: Department of Biochemistry, AP-HP, Hôpital Lariboisière, INSERM U942, Paris, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Launay
authors.affiliation: Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Yigal M
authors.initials: YM
authors.lastname: Pinto
authors.affiliation: Department of Biobehavioral Health, Pennsylvania State University, University Park, Pennsylvania, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Blizard
authors.affiliation: Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Connie R
authors.initials: CR
authors.lastname: Bezzina
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Paul
authors.initials: P
authors.lastname: Franken
authors.affiliation: Mary Lyon Centre, MRC Harwell, Harwell Science and Innovation Campus, Harwell, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Weaver
authors.affiliation: Mary Lyon Centre, MRC Harwell, Harwell Science and Innovation Campus, Harwell, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Wells
authors.affiliation: Mammalian Genetics Unit, MRC Harwell, Harwell Science and Innovation Campus, Harwell, UK.
authors.forename: Steve D M
authors.initials: SD
authors.lastname: Brown
authors.affiliation: Mammalian Genetics Unit, MRC Harwell, Harwell Science and Innovation Campus, Harwell, UK.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Potter
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Klenerman
authors.affiliation: School of Medicine, Medical Sciences and Nutrition, College of Life Sciences and Medicine, University of Aberdeen, Aberdeen, UK.
authors.forename: Arimantas
authors.initials: A
authors.lastname: Lionikas
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford, UK.|UCL Genetics Institute, University College London, London, UK.
authors.forename: Richard
authors.identifier: 0000-0002-1022-9330
authors.initials: R
authors.lastname: Mott
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford, UK.|Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Flint
mesh_terms: D000818:Animals; D021461:Animals, Outbred Strains / Q000235:genetics*; D002874:Chromosome Mapping; D005819:Genetic Markers / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D051379:Mice; D020412:Multifactorial Inheritance / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*
chemical_list: D005819:Genetic Markers