Article | Published:

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

Nature Genetics volume 45, pages 767775 (2013) | Download Citation

Abstract

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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Acknowledgements

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).

Author information

Affiliations

  1. Wellcome Trust Centre for Human Genetics, Oxford, UK.

    • Amelie Baud
    • , Regina Lopez-Aumatell
    • , Richard Mott
    •  & Jonathan Flint
  2. Hubrecht Institute, Koninklijke Nederlandse Akademie van Wetenschappen and University Medical Center Utrecht, Utrecht, The Netherlands.

    • Roel Hermsen
    • , Victor Guryev
    • , Nico Lansu
    • , Pim Toonen
    • , Frans Paul Ruzius
    • , Ewart de Bruijn
    •  & Edwin Cuppen
  3. European Research Institute for the Biology of Ageing, Rijksuniversiteit Groningen, Universitair Medisch Centrum Groningen, Groningen, The Netherlands.

    • Victor Guryev
  4. Neuroimmunology Unit, Department of Clinical Neuroscience, Centre for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.

    • Pernilla Stridh
    • , Margarita Diez
    • , Johan Ockinger
    • , Amennai D Beyeen
    • , Alan Gillett
    • , Nada Abdelmagid
    • , Andre Ortlieb Guerreiro-Cacais
    • , Maja Jagodic
    •  & Tomas Olsson
  5. British Heart Foundation (BHF) Glasgow Cardiovascular Research Centre, Institute of Cardiovascular & Medical Sciences, Glasgow University, Glasgow, UK.

    • Delyth Graham
    • , Martin W McBride
    • , Elisabeth Beattie
    • , Ngan Huynh
    • , William H Miller
    •  & Anna F Dominiczak
  6. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.

    • Tatiana Foroud
    •  & Daniel L Koller
  7. Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche Scientifique (UMRS) 872, Cordeliers Research Centre, Paris, France.

    • Sophie Calderari
    •  & Dominique Gauguier
  8. Department of Medical Biochemistry and Biophysics, Division of Medical Inflammation Research, Karolinska Institutet, Stockholm, Sweden.

    • Jonatan Tuncel
    • , Ulrika Norin
    • , Diana Ekman
    • , Martina Johannesson
    •  & Rikard Holmdahl
  9. Department of Orthopedic Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA.

    • Imranul Alam
  10. Max-Delbruck Center for Molecular Medicine, Berlin, Germany.

    • Samreen Falak
    • , Oliver Hummel
    • , Kathrin Saar
    • , Giannino Patone
    • , Anja Bauerfeind
    • , Matthias Heinig
    • , Young-Ae Lee
    • , Carola Rintisch
    • , Herbert Schulz
    •  & Norbert Hubner
  11. INSERM U698, Hôpital Bichat, Paris, France.

    • Mary Osborne-Pellegrin
  12. Medical Psychology Unit, Department of Psychiatry & Forensic Medicine, Institute of Neurosciences, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.

    • Esther Martinez-Membrives
    • , Toni Canete
    • , Gloria Blazquez
    • , Elia Vicens-Costa
    • , Carme Mont-Cardona
    • , Sira Diaz-Moran
    • , Adolf Tobena
    • , Regina Lopez-Aumatell
    •  & Alberto Fernandez-Teruel
  13. Commissariat à l'Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry, France.

    • Diana Zelenika
    • , Marie-Therese Bihoreau
    •  & Mark Lathrop
  14. Department of Computational Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany.

    • Matthias Heinig
  15. Pediatric Allergology, Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin, Berlin, Germany.

    • Young-Ae Lee
  16. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.

    • David A Wheeler
    • , Kim C Worley
    • , Donna M Muzny
    •  & Richard A Gibbs
  17. The Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

    • Heidi Hauser
    • , David J Adams
    •  & Thomas Keane
  18. Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK.

    • Santosh S Atanur
    •  & Tim J Aitman
  19. European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge, UK.

    • Paul Flicek
  20. Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Tomas Malinauskas
    •  & E Yvonne Jones
  21. DZHK (German Centre for Cardiovascular Research), Partner site Berlin, Berlin, Germany.

    • Norbert Hubner

Consortia

  1. Rat Genome Sequencing and Mapping Consortium

Authors

    Contributions

    The writing group included A. Baud, R. Hermsen, V.G., D. Gauguier, P.S., T.O., R. Holmdahl, D. Graham, M.W.M., T.F., A.F.-T., N. Hubner, E.C., R.M. and J.F. The phenotyping group included S.C., D. Gauguier, P.S., M.D., J.O., A.D.B., A.G., N.A., A.O.G.-C., M. Jagodic, T.O., M. Johannesson, J.T., U.N., R. Holmdahl, D. Graham, E.B., N. Huynh, W.H.M., M.W.M., A.F.D., D.L.K., T.F., I.A., S.F., N. Hubner, M.O.-P., E.M.-M., R.L.-A., T.C., G.B., E.V.-C., C.M.-C., S.D.-M., A.T. and A.F.-T. The high-density genotyping array design and analysis group included O.H., D.Z., K.S., G.P., A. Bauerfeind, M.-T.B., M.H., Y.-A.L., C.R., H.S., D.A.W., K.C.W., D.M.M., R.A.G., M.L. and N. Hubner. The sequencing group included R. Hermsen, O.H., N.L., G.P., P.T., F.P.R., E.d.B., H.H., S.S.A., T.J.A., P.F., D.J.A., T.K., K.S., N. Hubner, V.G. and E.C. The protein structure group included T.M. and E.Y.J. QTL data analysis was performed by A. Baud, J.F., D.E. and R.M. The project was coordinated by A. Baud, R.L.-A., A.F.D., N. Hubner, M. Johannesson, R. Holmdahl, T.O., D. Gauguier, A.F.-T., R.M., E.C. and J.F.

    Competing interests

    The author declare no competing financial interests.

    Corresponding authors

    Correspondence to Alberto Fernandez-Teruel or Edwin Cuppen or Richard Mott or Jonathan Flint.

    Supplementary information

    PDF files

    1. 1.

      Supplementary Text and Figures

      Supplementary Figures 1–4, Supplementary Tables 2 and 4, Supplementary Note

    Excel files

    1. 1.

      Supplementary Table 1

      Phenotypes collected, covariates, normalization procedure, mapping method, threshold used for 10% FDR, and number of animals with phenotypic values.

    2. 2.

      Supplementary Table 3

      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)

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    DOI

    https://doi.org/10.1038/ng.2644

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