Article abstract

Nature Genetics 41, 35 - 46 (2008)
Published online: 7 December 2008 | doi:10.1038/ng.271

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

Chiara Sabatti1,2,28, Susan K Service3,28, Anna-Liisa Hartikainen4, Anneli Pouta5, Samuli Ripatti6, Jae Brodsky2, Chris G Jones3,7, Noah A Zaitlen7, Teppo Varilo8,9, Marika Kaakinen10, Ulla Sovio11, Aimo Ruokonen12, Jaana Laitinen13, Eveliina Jakkula6, Lachlan Coin11, Clive Hoggart11, Andrew Collins14, Hannu Turunen6, Stacey Gabriel15, Paul Elliot11, Mark I McCarthy16,17,18, Mark J Daly15,19,20,21,22,23, Marjo-Riitta Järvelin5,11,24, Nelson B Freimer3,25,26 & Leena Peltonen6,15,27

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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  1. Department of Human Genetics and Los Angeles, Los Angeles, California 90095, USA.
  2. Department of Statistics, University of California, Los Angeles, Los Angeles, California 90095, USA.
  3. Center for Neurobehavioral Genetics, University of California, Los Angeles, Los Angeles, California 90095, USA.
  4. Department of Obstetrics and Gynaecology, University of Oulu, Fin-90220, Oulu, Finland.
  5. National Public Health Institute, Department of Child and Adolescent Health, Box 310, FIN-90101 Oulu, Finland.
  6. Institute for Molecular Medicine (FIMM), P.O. Box 20, FIN-00014 University of Helsinki, Finland.
  7. Department of Computer Science, University of California, Los Angeles, Los Angeles, California 90095, USA.
  8. Department of Medical Genetics, University of Helsinki, Helsinki, Finland.
  9. Department of Molecular Medicine, National Public Health Institute, Biomedicum Helsinki, 00290 Helsinki, Finland.
  10. Institute of Health Sciences, P.O. Box 5000, 90014 University of Oulu, Fin-90220, Oulu, Finland.
  11. Department of Epidemiology and Public Health, Imperial College London, Norfolk Place, St. Mary's Campus, London W2 1PG, UK.
  12. Department of Clinical Chemistry, University of Oulu, Fin-90220, Oulu, Finland.
  13. Finnish Institute of Occupational Health, Aapistie 1, Fin-90220, Oulu, Finland.
  14. Human Genetics Research Division, University of Southampton, Southampton General Hospital, Duthie Building (808), Tremona Road, Southampton SO16 6YA, UK.
  15. Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
  16. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Old Road, Headington, Oxford OX3 7LJ, UK.
  17. Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Headington, Oxford OX3 7BN, UK.
  18. Oxford NIHR Biomedical Research Centre, Churchill Hospital, Old Road, Headington, Oxford OX3 7LJ, UK.
  19. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114,USA.
  20. Departments of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
  21. Psychiatry and Harvard Medical School, Boston, Massachusetts 02115, USA.
  22. Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
  23. Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
  24. Institute of Health Sciences and Biocenter Oulu, University of Oulu, Box 5000, Fin-90014, Oulu Finland.
  25. The Jane and Terry Semel Institute for Neuroscience and Human Behavior and Los Angeles, Los Angeles, California 90095, USA.
  26. Department of Psychiatry, University of California, Los Angeles, Los Angeles, California 90095, USA.
  27. Wellcome Trust Sanger Institute, Cambridge, CB10 1HH, UK.
  28. These authors contributed equally to this work.

Correspondence to: Nelson B Freimer3,25,26 e-mail: nfreimer@mednet.ucla.edu

Correspondence to: Leena Peltonen6,15,27 e-mail: leena@sanger.ac.uk



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