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

Nature Genetics volume 45, pages 767–775 (2013)Cite this article

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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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Figure 1: Sequence diversity among progenitor strains and genetic architecture of the rat NIH-HS.
Figure 2: Genome scan for platelet aggregation.
Figure 3: Merge analysis to identify causative genes and sequence variants.
Figure 4: Simulation of causal variants.

Accession codes

Primary accessions

European Nucleotide Archive

NCBI Reference Sequence

Referenced accessions

Protein Data Bank

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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

Authors and 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. Department of Clinical Neuroscience, Neuroimmunology Unit, 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. Department of Psychiatry & Forensic Medicine, Medical Psychology Unit, 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

Rat Genome Sequencing and Mapping Consortium

  • Amelie Baud
  • , Roel Hermsen
  • , Victor Guryev
  • , Pernilla Stridh
  • , Delyth Graham
  • , Martin W McBride
  • , Tatiana Foroud
  • , Sophie Calderari
  • , Margarita Diez
  • , Johan Ockinger
  • , Amennai D Beyeen
  • , Alan Gillett
  • , Nada Abdelmagid
  • , Andre Ortlieb Guerreiro-Cacais
  • , Maja Jagodic
  • , Jonatan Tuncel
  • , Ulrika Norin
  • , Elisabeth Beattie
  • , Ngan Huynh
  • , William H Miller
  • , Daniel L Koller
  • , Imranul Alam
  • , Samreen Falak
  • , Mary Osborne-Pellegrin
  • , Esther Martinez-Membrives
  • , Toni Canete
  • , Gloria Blazquez
  • , Elia Vicens-Costa
  • , Carme Mont-Cardona
  • , Sira Diaz-Moran
  • , Adolf Tobena
  • , Oliver Hummel
  • , Diana Zelenika
  • , Kathrin Saar
  • , Giannino Patone
  • , Anja Bauerfeind
  • , Marie-Therese Bihoreau
  • , Matthias Heinig
  • , Young-Ae Lee
  • , Carola Rintisch
  • , Herbert Schulz
  • , David A Wheeler
  • , Kim C Worley
  • , Donna M Muzny
  • , Richard A Gibbs
  • , Mark Lathrop
  • , Nico Lansu
  • , Pim Toonen
  • , Frans Paul Ruzius
  • , Ewart de Bruijn
  • , Heidi Hauser
  • , David J Adams
  • , Thomas Keane
  • , Santosh S Atanur
  • , Tim J Aitman
  • , Paul Flicek
  • , Tomas Malinauskas
  • , E Yvonne Jones
  • , Diana Ekman
  • , Regina Lopez-Aumatell
  • , Anna F Dominiczak
  • , Martina Johannesson
  • , Rikard Holmdahl
  • , Tomas Olsson
  • , Dominique Gauguier
  • , Norbert Hubner
  • , Alberto Fernandez-Teruel
  • , Edwin Cuppen
  • , Richard Mott
  •  & Jonathan Flint

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.

Corresponding authors

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

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Competing interests

The author declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4, Supplementary Tables 2 and 4, Supplementary Note (PDF 2186 kb)

Supplementary Table 1

Phenotypes collected, covariates, normalization procedure, mapping method, threshold used for 10% FDR, and number of animals with phenotypic values. (XLS 58 kb)

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) (XLS 81 kb)

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Rat Genome Sequencing and Mapping Consortium. Combined sequence-based and genetic mapping analysis of complex traits in outbred rats. Nat Genet 45, 767–775 (2013). https://doi.org/10.1038/ng.2644

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