Genetic mapping on fully sequenced individuals is transforming understanding of the relationship between molecular variation and variation in complex traits. Here we report a combined sequence and genetic mapping analysis in outbred rats that maps 355 quantitative trait loci for 122 phenotypes. We identify 35 causal genes involved in 31 phenotypes, implicating new genes in models of anxiety, heart disease and multiple sclerosis. The relationship between sequence and genetic variation is unexpectedly complex: at approximately 40% of quantitative trait loci, a single sequence variant cannot account for the phenotypic effect. Using comparable sequence and mapping data from mice, we show that the extent and spatial pattern of variation in inbred rats differ substantially from those of inbred mice and that the genetic variants in orthologous genes rarely contribute to the same phenotype in both species.
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European Nucleotide Archive
NCBI Reference Sequence
Protein Data Bank
We are grateful to T. Serikawa (Kyoto University) for the LE/Stm BAC clones. The Human Genome Sequencing Center sequence production teams at the Baylor College of Medicine produced the Sanger sequencing data for the eight sequenced strains used to define the RATDIV SNP genotyping array (see ref. 8 for a list of Baylor College of Medicine HGSC sequencing contributors). We thank E. Redei for providing the NIH-HS rat colony. The funders we would like to acknowledge are as follows: the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement HEALTH-F4-2010-241504 (EURATRANS); The Wellcome Trust (090532/Z/09/Z, 083573/Z/07/Z, 089269/Z/09/Z); The Swedish Research Council (grant K2008-66X-20776-01-4); the Harald and Greta Jeanssons Foundation; The Swedish Association for Persons with Neurological Disabilities; the Åke Wibergs Foundation; the Åke Löwnertz Foundation; Karolinska Institutet funds; the European Union's Sixth Framework Programme EURATools (grant LSHG-CT-2005-019015); the Bibbi and Nils Jensens Foundation; the Söderbergs Foundation; and the Knut and Alice Wallenbergs Foundation. We also thank the Ministerio de Ciencia e Innovación (reference PSI2009-10532 and the Formación de Personal Investigador fellowship to C.M.-C.); the Fundació La Maratò TV3 (reference 092630); the Direcció General de la Recerca (reference 2009SGR-0051); and the British Heart Foundation (BHFRG/07/005/23633). T.J.A. and S.S.A. acknowledge funding from the Imperial BHF Centre of Research Excellence. M. Johannesson acknowledges support from Prof. Nanna Svartz Foundation, The Swedish Rheumatism Association and The King Gustaf V 80th Anniversary Foundation. D. Gauguier acknowledges support from the Institute of Cardiometabolism and Nutrition (ICAN; ANR-10-IAHU-05). T.M. and E.Y.J. acknowledge support from Cancer Research UK (A10976) and the UK Medical Research Council (G9900061). T.F., D.L.K. and I.A. acknowledge support from the U.S. National Institutes of Health (R01 AR047822).
Phenotypes collected, covariates, normalization procedure, mapping method, threshold used for 10% FDR, and number of animals with phenotypic values.
QTLs mapped in the NIH-HS, with coordinates, association values, effect sizes, and presence or absence of candidate variants (for the phenotypes mapped using mixed models)