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Genome-wide association analysis of metabolic traits in a birth cohort from a founder population

Nature Genetics volume 41, pages 35–46 (2009)Cite this article

Abstract

Genome-wide association studies (GWAS) of longitudinal birth cohorts enable joint investigation of environmental and genetic influences on complex traits. We report GWAS results for nine quantitative metabolic traits (triglycerides, high-density lipoprotein, low-density lipoprotein, glucose, insulin, C-reactive protein, body mass index, and systolic and diastolic blood pressure) in the Northern Finland Birth Cohort 1966 (NFBC1966), drawn from the most genetically isolated Finnish regions. We replicate most previously reported associations for these traits and identify nine new associations, several of which highlight genes with metabolic functions: high-density lipoprotein with NR1H3 (LXRA), low-density lipoprotein with AR and FADS1-FADS2, glucose with MTNR1B, and insulin with PANK1. Two of these new associations emerged after adjustment of results for body mass index. Gene–environment interaction analyses suggested additional associations, which will require validation in larger samples. The currently identified loci, together with quantified environmental exposures, explain little of the trait variation in NFBC1966. The association observed between low-density lipoprotein and an infrequent variant in AR suggests the potential of such a cohort for identifying associations with both common, low-impact and rarer, high-impact quantitative trait loci.

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Figure 1: Linguistic/geographic groups of Northern Finland and their genetic signature.
Figure 2: Quantile-quantile plots of the tails of the P-value distribution for the nine traits.
Figure 3: Association P values for genotyped SNPs for the nine traits.
Figure 4: Association signal in the nine newly identified loci.
Figure 5: Graphical representation of the proportion of explained variance for each of the five traits for which genetic loci have been identified.

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Acknowledgements

We acknowledge the support of US National Heart, Lung, and Blood Institute grant HL087679 through the STAMPEED program, grants MH083268, GM053275-14 and U54 RR020278 from the US National Institutes of Health, grant DMS-0239427 from the National Science Foundation, the Medical Research Council of the UK, EURO-BLCS, QLG1-CT-2000-01643 and the European Community's Seventh Framework Programme (FP7/2007-2013), ENGAGE project and grant agreement HEALTH-F4-2007-201413. The authors would like to thank the Center of Excellence in Common Disease Genetics of the Academy of Finland and Nordic Center of Excellence in Disease Genetics, the Sydantautisaatio (Finnish Foundation of Heart Diseases), the Broad Genotyping Center, D. Mirel, H. Hobbs, J. DeYoung, P. Rantakallio, M. Koiranen and M. Isohanni for advice and assistance.

Author information

Author notes

  1. Chiara Sabatti and Susan K Service: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Human Genetics and Los Angeles, Los Angeles, 90095, California, USA

    Chiara Sabatti

  2. Department of Statistics, University of California, Los Angeles, Los Angeles, 90095, California, USA

    Chiara Sabatti & Jae Brodsky

  3. Center for Neurobehavioral Genetics, University of California, Los Angeles, Los Angeles, 90095, California, USA

    Susan K Service, Chris G Jones & Nelson B Freimer

  4. Department of Obstetrics and Gynaecology, University of Oulu, Oulu, Fin-90220, Finland

    Anna-Liisa Hartikainen

  5. Department of Child and Adolescent Health, National Public Health Institute, Box 310, Oulu, FIN-90101, Finland

    Anneli Pouta & Marjo-Riitta Järvelin

  6. Institute for Molecular Medicine (FIMM), P.O. Box 20, FIN-00014 University of Helsinki, Finland

    Samuli Ripatti, Eveliina Jakkula, Hannu Turunen & Leena Peltonen

  7. Department of Computer Science, University of California, Los Angeles, Los Angeles, 90095, California, USA

    Chris G Jones & Noah A Zaitlen

  8. Department of Medical Genetics, University of Helsinki, Helsinki, Finland

    Teppo Varilo

  9. Department of Molecular Medicine, National Public Health Institute, Biomedicum Helsinki, 00290, Helsinki, Finland

    Teppo Varilo

  10. Institute of Health Sciences, P.O. Box 5000, 90014 University of Oulu, Oulu, Fin-90220, Finland

    Marika Kaakinen

  11. Department of Epidemiology and Public Health, Imperial College London, Norfolk Place, St. Mary's Campus, London, W2 1PG, UK

    Ulla Sovio, Lachlan Coin, Clive Hoggart, Paul Elliot & Marjo-Riitta Järvelin

  12. Department of Clinical Chemistry, University of Oulu, Oulu, Fin-90220, Finland

    Aimo Ruokonen

  13. Finnish Institute of Occupational Health, Aapistie 1, Oulu, Fin-90220, Finland

    Jaana Laitinen

  14. Human Genetics Research Division, University of Southampton, Southampton General Hospital, Duthie Building (808), Tremona Road, Southampton, SO16 6YA, UK

    Andrew Collins

  15. Broad Institute of Harvard and MIT, Cambridge, 02142, Massachusetts, USA

    Stacey Gabriel, Mark J Daly & Leena Peltonen

  16. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Old Road, Headington, OX3 7LJ, Oxford, UK

    Mark I McCarthy

  17. Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Headington, OX3 7BN, Oxford, UK

    Mark I McCarthy

  18. Oxford NIHR Biomedical Research Centre, Churchill Hospital, Old Road, Headington, OX3 7LJ, Oxford, UK

    Mark I McCarthy

  19. Center for Human Genetic Research, Massachusetts General Hospital, Boston, 02114, Massachusetts, USA

    Mark J Daly

  20. Departments of Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Mark J Daly

  21. Psychiatry and Harvard Medical School, Boston, 02115, Massachusetts, USA

    Mark J Daly

  22. Medicine, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Mark J Daly

  23. Department of Medicine, Massachusetts General Hospital, Boston, 02114, Massachusetts, USA

    Mark J Daly

  24. Institute of Health Sciences and Biocenter Oulu, University of Oulu, Box 5000, Oulu, Fin-90014, Finland

    Marjo-Riitta Järvelin

  25. The Jane and Terry Semel Institute for Neuroscience and Human Behavior and Los Angeles, Los Angeles, 90095, California, USA

    Nelson B Freimer

  26. Department of Psychiatry, University of California, Los Angeles, Los Angeles, 90095, California, USA

    Nelson B Freimer

  27. Wellcome Trust Sanger Institute, Cambridge, CB10 1HH, UK

    Leena Peltonen

Authors
  1. Chiara Sabatti
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Contributions

The study was designed by L.P., N.B.F., C.S., M.I.M., M.J.D., P.E., M.-R.J. and S.K.S. Information on traits was collected and maintained by M.-R.J., A.-L.H., A.P., A.R. and J.L. Genotyping was supervised by S.G. Database support was provided by H.T., U.S. and M.K. Statistical analysis was performed by C.S., S.K.S., A.C., C.G.J., J.B., N.A.Z., and M.J.D. S.R., E.J. and T.V. contributed to the analysis of the Finnish genetic signature. L.C., C.H. and P.E. participated in discussion of results. The manuscript was written by C.S., S.K.S., N.B.F. and L.P. All authors reviewed the manuscript.

Corresponding authors

Correspondence to Nelson B Freimer or Leena Peltonen.

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Sabatti, C., Service, S., Hartikainen, AL. et al. Genome-wide association analysis of metabolic traits in a birth cohort from a founder population. Nat Genet 41, 35–46 (2009). https://doi.org/10.1038/ng.271

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