Article abstract

Nature Genetics 41, 47 - 55 (2008)
Published online: 7 December 2008 | doi:10.1038/ng.269

Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts

Yurii S Aulchenko1,37, Samuli Ripatti2,3,37, Ida Lindqvist2,3, Dorret Boomsma4, Iris M Heid5,6, Peter P Pramstaller7,8,9, Brenda W J H Penninx10, A Cecile J W Janssens1, James F Wilson11,12, Tim Spector13, Nicholas G Martin14, Nancy L Pedersen15, Kirsten Ohm Kyvik16, Jaakko Kaprio3,17,18, Albert Hofman1, Nelson B Freimer19, Marjo-Riitta Jarvelin20,21, Ulf Gyllensten22, Harry Campbell11, Igor Rudan11,23,24, Åsa Johansson22, Fabio Marroni7, Caroline Hayward12, Veronique Vitart12, Inger Jonasson22, Cristian Pattaro7, Alan Wright12, Nick Hastie12, Irene Pichler7, Andrew A Hicks7, Mario Falchi13,25, Gonneke Willemsen4, Jouke-Jan Hottenga4, Eco J C de Geus4, Grant W Montgomery14, John Whitfield14, Patrik Magnusson15, Juha Saharinen3, Markus Perola2, Kaisa Silander2, Aaron Isaacs1, Eric J G Sijbrands1,26, Andre G Uitterlinden26, Jacqueline C M Witteman1, Ben A Oostra27, Paul Elliott20, Aimo Ruokonen28, Chiara Sabatti29, Christian Gieger5, Thomas Meitinger30,31, Florian Kronenberg32, Angela Döring5, H-Erich Wichmann5,6, Johannes H Smit10, Mark I McCarthy33,34, Cornelia M van Duijn1 & Leena Peltonen2,3,35,36 for the ENGAGE Consortium

Recent genome-wide association (GWA) studies of lipids have been conducted in samples ascertained for other phenotypes, particularly diabetes. Here we report the first GWA analysis of loci affecting total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides sampled randomly from 16 population-based cohorts and genotyped using mainly the Illumina HumanHap300-Duo platform. Our study included a total of 17,797–22,562 persons, aged 18–104 years and from geographic regions spanning from the Nordic countries to Southern Europe. We established 22 loci associated with serum lipid levels at a genome-wide significance level (P < 5 times 10-8), including 16 loci that were identified by previous GWA studies. The six newly identified loci in our cohort samples are ABCG5 (TC, P = 1.5 times 10-11; LDL, P = 2.6 times 10-10), TMEM57 (TC, P = 5.4 times 10-10), CTCF-PRMT8 region (HDL, P = 8.3 times 10-16), DNAH11 (LDL, P = 6.1 times 10-9), FADS3-FADS2 (TC, P = 1.5 times 10-10; LDL, P = 4.4 times 10-13) and MADD-FOLH1 region (HDL, P = 6 times 10-11). For three loci, effect sizes differed significantly by sex. Genetic risk scores based on lipid loci explain up to 4.8% of variation in lipids and were also associated with increased intima media thickness (P = 0.001) and coronary heart disease incidence (P = 0.04). The genetic risk score improves the screening of high-risk groups of dyslipidemia over classical risk factors.

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  1. Department of Epidemiology and Biostatistics, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
  2. National Public Health Institute, Biomedicum, P.O. Box 104, 00251 Helsinki, Finland.
  3. FIMM, Institute for Molecular Medicine, Finland, Biomedicum, P.O.Box 104, 00251 Helsinki, Finland.
  4. Department of Biological Psychology, VU University Amsterdam, Van der Boechorststraat 1, 1081 BT Amsterdam, The Netherlands.
  5. Helmholtz-Center Munich, Institute of Epidemiology, Ingolstädter Landstras zlige 1, D-85764 Neuherberg, Germany.
  6. University of Munich, IBE, Chair of Epidemiology, D-81377 Munich, German.
  7. Institute of Genetic Medicine, EURAC research, Viale Druso 1, 39100 Bolzano, Italy.
  8. Department of Neurology, General Central Hospital, Via Bohler 5, 39100 Bolzano, Italy.
  9. Department of Neurology, University of Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany.
  10. Department of Psychiatry, EMGO Institute, Institute of Neuroscience, VU Medical Center, Amsterdam, The Netherlands.
  11. Public Health Sciences, Community Health Sciences, University of Edinburgh, Medical School, Teviot Place, Edinburgh EH8 9AG, UK.
  12. MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Edinburgh, EH4 2XU, UK.
  13. Twin Research and Genetic Epidemiology Unit, King's College London, St Thomas' Hospital Campus, Strand, London WC2R 2LS, UK.
  14. Genetic Epidemiology Unit, Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Queensland, Australia 4029.
  15. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 17177 Stockholm, Sweden.
  16. Institute of Regional Health Research and the Danish Twin Registry, Institute of Public Health, University of Southern Denmark, J. B. Winsløws Vej 9B, DK-5000, Odense, Denmark.
  17. Faculty of Medicine, Department of Public Health, P.O. Box 41, FIN-00014 University of Helsinki, Helsinki, Finland.
  18. Department of Mental Health and Alcohol Research, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland.
  19. Department of Psychiatry, Center for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, 695 Charles E. Young Drive South, Room 3506, Los Angeles, California 90095, USA.
  20. Department of Epidemiology and Public Health, Imperial College London, St Mary's Campus, Norfolk Place, London W2 1PG, UK.
  21. Department of Public Health Science and General Practice, University of Oulu, Finland.
  22. Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, S-751 85 Uppsala, Sweden.
  23. Croatian Centre for Global Health, University of Split Medical School, Soltanska 2, 21000 Split, Croatia.
  24. Institute for Clinical Medical Research, University Hospital "Sestre Milosrdnice", Vinogradska 29, 10000 Zagreb. CROATIA.
  25. Genomic Medicine, Imperial College London, South Kensington Campus, London SW7 2AZ, UK.
  26. Department of Internal Medicine, Erasmus University Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.
  27. Department of Clinical Genetics. Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
  28. Department of Biochemistry, University Hospital Oulu, 90220 Oulu, Finland.
  29. Department of Human Genetics, UCLA School of Medicine, University of California, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA.
  30. Helmholtz-Center Munich, Institute of Human Genetics, Ingolstädter Landstras zlige 1, D-85764 Neuherberg, Germany.
  31. Technical University Munich, Institute of Human Genetics, D-81675, Munich, Germany.
  32. Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Schoepfstrasse 41, A-6020 Innsbruck, Austria.
  33. Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
  34. Oxford Centre for Diabetes, Endocrinology and Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
  35. The Broad Institute, Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
  36. Wellcome Trust Sanger Institute Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
  37. These authors contributed equally to this work.

Correspondence to: e-mail: leena@sanger.ac.uk



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