Combined sequence-based and genetic mapping analysis of complex traits in outbred rats

• Published in: Nature genetics Vol. 45; no. 7; pp. 767 - 775
• Main Authors: Baud, Amelie, Hermsen, Roel, Guryev, Victor, Stridh, Pernilla, Graham, Delyth, McBride, Martin W, Foroud, Tatiana, Calderari, Sophie, Diez, Margarita, Ockinger, Johan, Beyeen, Amennai D, Gillett, Alan, Abdelmagid, Nada, Guerreiro-Cacais, Andre Ortlieb, Jagodic, Maja, Tuncel, Jonatan, Norin, Ulrika, Beattie, Elisabeth, Huynh, Ngan, Miller, William H, Koller, Daniel L, Alam, Imranul, Falak, Samreen, Osborne-Pellegrin, Mary, Martinez-Membrives, Esther, Canete, Toni, Blazquez, Gloria, Vicens-Costa, Elia, Mont-Cardona, Carme, Diaz-Moran, Sira, Tobena, Adolf, Hummel, Oliver, Zelenika, Diana, Saar, Kathrin, Patone, Giannino, Bauerfeind, Anja, Bihoreau, Marie-Therese, Heinig, Matthias, Lee, Young-Ae, Rintisch, Carola, Schulz, Herbert, Wheeler, David A, Worley, Kim C, Muzny, Donna M, Gibbs, Richard A, Lathrop, Mark, Lansu, Nico, Toonen, Pim, Ruzius, Frans Paul, de Bruijn, Ewart, Hauser, Heidi, Adams, David J, Keane, Thomas, Atanur, Santosh S, Aitman, Tim J, Flicek, Paul, Malinauskas, Tomas, Jones, E Yvonne, Ekman, Diana, Lopez-Aumatell, Regina, Dominiczak, Anna F, Johannesson, Martina, Holmdahl, Rikard, Olsson, Tomas, Gauguier, Dominique, Hubner, Norbert, Fernandez-Teruel, Alberto, Cuppen, Edwin, Mott, Richard, Flint, Jonathan
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2013; Nature Publishing Group
• Subjects: 631/208/205/2138; 631/208/514/1948; Agriculture; Animal Genetics and Genomics; Animals; Animals, Outbred Strains; Anxiety - genetics; Biomedicine; Cancer Research; Cardiovascular diseases; Chromosome mapping; Chromosome Mapping - methods; Diagnosis; Endocrinology and metabolism; Gene Function; Gene mapping; Genetic aspects; Genetic diversity; Genetic variance; Genetic Variation - genetics; Genetics; Genomes; Genomics; Genotype; Haplotypes; Heart Diseases - genetics; Human Genetics; Human health and pathology; Humans; Klinisk medicin; Life Sciences; Medical research; Medicin och hälsovetenskap; Medicinsk bioteknologi; Medicinsk bioteknologi (inriktn. mot cellbiologi (inkl. stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci); Medicinsk genetik; Medicinska och farmaceutiska grundvetenskaper; Methods; Mice; Mice, Inbred C57BL; Models, Molecular; Multiple sclerosis; Multiple Sclerosis - genetics; Neurologi; Phenotype; Polymorphism, Single Nucleotide; Quantitative trait loci; Quantitative Trait Loci - genetics; Rats; Sequence Analysis, DNA - methods; Germany
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.2644

The Rat Genome Sequencing and Mapping Consortium reports a combined sequence-based and genetic mapping analysis of 160 phenotypes in an outbred rat heterogeneous stock. They identify 31 genes involved in 27 different phenotypes. 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.