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

Nature Genetics 41, 47–55 (2009) | Download Citation

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Abstract

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 × 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 × 10−11; LDL, P = 2.6 × 10−10), TMEM57 (TC, P = 5.4 × 10−10), CTCF-PRMT8 region (HDL, P = 8.3 × 10−16), DNAH11 (LDL, P = 6.1 × 10−9), FADS3-FADS2 (TC, P = 1.5 × 10−10; LDL, P = 4.4 × 10−13) and MADD-FOLH1 region (HDL, P = 6 × 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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Acknowledgements

Above all, we thank study participants for making this work possible. We thank H.-Y. Shen and M. Allen for ENGAGE project management and M. Krestyaninova for IT-system setup.

The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F4-2007-201413 by the European Commission under the programme 'Quality of Life and Management of the Living Resources' of 5th Framework Programme (no. QLG2-CT-2002-01254). The Finnish Heart Association (M.P., L.P.) is gratefully acknowledged for its financial support. L.P. and J.K. have been supported by the Academy of Finland Centre of Excellence in Complex Disease Genetics.

NFBC genotyping was supported on NHLBI grant 5R01HL087679-02 through the STAMPEED program.

EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP grant number 018947 (LSHG-CT-2006-01947).

For the MICROS study in South Tyrol, we thank the primary care practitioners R. Stocker, S. Waldner, T. Pizzecco, J. Plangger, U. Marcadent and the personnel of the Hospital of Silandro (Department of Laboratory Medicine) for their participation and collaboration in the research project. In South Tyrol, the study was supported by the Ministry of Health of the Autonomous Province of Bolzano and the South Tyrolean Sparkasse Foundation.

NTR/NESDA was supported by “Genetic basis of anxiety and depression” program (NWO 904-61-090); Twin-family database for behavior genomics studies (NWO 480-04-004); Center for Medical Systems Biology (NWO Genomics); Spinozapremie (SPI 56-464-14192); Centre for Neurogenomics and Cognitive Research (CNCR-VU); Genome-wide analyses of European twin and population cohorts (EU/QLRT-2001-01254); Geestkracht program of ZonMW (10-000-1002); and matching funds from universities and mental health care institutes involved in NESDA (GGZ Buitenamstel-Geestgronden, Rivierduinen, University Medical Center Groningen, GGZ Lentis, GGZ Friesland, GGZ Drenthe). Major funding for this project is from the Genetic Association Information Network of the Foundation for the US National Institutes of Health, a public-private partnership between the NIH and Pfizer, Affymetrix and Abbott Laboratories.

The MONICA/KORA Augsburg studies were financed by the Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany and supported by grants from the German Federal Ministry of Education and Research (BMBF). Part of this work was financed by the German National Genome Research Network (NGFN) and by the “Genomics of Lipid-associated Disorders – GOLD” of the “Austrian Genome Research Programme GEN-AU”. The KORA research was supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. We gratefully acknowledge the contribution of P. Lichtner, G. Eckstein and T. Strom and all other members of the Helmholtz Zentrum München genotyping staff in generating and analyzing the SNP dataset. We thank all members of field staffs who were involved in the planning and conduct of the MONICA/KORA Augsburg studies. Finally, we express our appreciation to all study participants.

Genome-wide genotyping of the Rotterdam Study was supported by NWO (175.010.2005.011). The Vis study in the Croatian island of Vis was supported through the grants from the Medical Research Council UK to H.C., A.W. and I.R.; and Ministry of Science, Education and Sport of the Republic of Croatia to I.R. (number 108-1080315-0302). The ERF study was supported by grants from The Netherlands Organisation for Scientific Research, Erasmus MC and the Centre for Medical Systems Biology (CMSB). We are grateful to all study participants and their relatives, general practitioners and neurologists for their contributions and to P. Veraart for her help in genealogy, J. Vergeer for the supervision of the laboratory work and P. Snijders for his help in data collection. The Northern Swedish Population Health Study was funded by the Swedish Medical Research Council and the European Commission through the EUROSPAN project. We are greatly indebted to the participants in the study. The ORCADES study was supported by the Scottish Executive Health Department, the Royal Society and the Wellcome Trust Clinical Research Facility. We would like to acknowledge the data collection team in Orkney, the clerical team in Edinburgh and the people of Orkney.

Author information

    • Yurii S Aulchenko
    •  & Samuli Ripatti

    These authors contributed equally to this work.

Affiliations

  1. Department of Epidemiology and Biostatistics, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.

    • Yurii S Aulchenko
    • , A Cecile J W Janssens
    • , Albert Hofman
    • , Aaron Isaacs
    • , Eric J G Sijbrands
    • , Jacqueline C M Witteman
    •  & Cornelia M van Duijn

  2. National Public Health Institute, Biomedicum, P.O. Box 104, 00251 Helsinki, Finland.

    • Samuli Ripatti
    • , Ida Lindqvist
    • , Markus Perola
    • , Kaisa Silander
    •  & Leena Peltonen

  3. FIMM, Institute for Molecular Medicine, Finland, Biomedicum, P.O.Box 104, 00251 Helsinki, Finland.

    • Samuli Ripatti
    • , Ida Lindqvist
    • , Jaakko Kaprio
    • , Juha Saharinen
    •  & Leena Peltonen

  4. Department of Biological Psychology, VU University Amsterdam, Van der Boechorststraat 1, 1081 BT Amsterdam, The Netherlands.

    • Dorret Boomsma
    • , Gonneke Willemsen
    • , Jouke-Jan Hottenga
    •  & Eco J C de Geus

  5. Helmholtz-Center Munich, Institute of Epidemiology, Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany.

    • Iris M Heid
    • , Christian Gieger
    • , Angela Döring
    •  & H-Erich Wichmann

  6. University of Munich, IBE, Chair of Epidemiology, D-81377 Munich, German.

    • Iris M Heid
    •  & H-Erich Wichmann

  7. Institute of Genetic Medicine, EURAC research, Viale Druso 1, 39100 Bolzano, Italy.

    • Peter P Pramstaller
    • , Fabio Marroni
    • , Cristian Pattaro
    • , Irene Pichler
    •  & Andrew A Hicks

  8. Department of Neurology, General Central Hospital, Via Bohler 5, 39100 Bolzano, Italy.

    • Peter P Pramstaller

  9. Department of Neurology, University of Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany.

    • Peter P Pramstaller

  10. Department of Psychiatry, EMGO Institute, Institute of Neuroscience, VU Medical Center, Amsterdam, The Netherlands.

    • Brenda W J H Penninx
    •  & Johannes H Smit

  11. Public Health Sciences, Community Health Sciences, University of Edinburgh, Medical School, Teviot Place, Edinburgh EH8 9AG, UK.

    • James F Wilson
    • , Harry Campbell
    •  & Igor Rudan

  12. MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Edinburgh, EH4 2XU, UK.

    • James F Wilson
    • , Caroline Hayward
    • , Veronique Vitart
    • , Alan Wright
    •  & Nick Hastie

  13. Twin Research and Genetic Epidemiology Unit, King's College London, St Thomas' Hospital Campus, Strand, London WC2R 2LS, UK.

    • Tim Spector
    •  & Mario Falchi

  14. Genetic Epidemiology Unit, Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Queensland, Australia 4029.

    • Nicholas G Martin
    • , Grant W Montgomery
    •  & John Whitfield

  15. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 17177 Stockholm, Sweden.

    • Nancy L Pedersen
    •  & Patrik Magnusson

  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.

    • Kirsten Ohm Kyvik

  17. Faculty of Medicine, Department of Public Health, P.O. Box 41, FIN-00014 University of Helsinki, Helsinki, Finland.

    • Jaakko Kaprio

  18. Department of Mental Health and Alcohol Research, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland.

    • Jaakko Kaprio

  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.

    • Nelson B Freimer

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

    • Marjo-Riitta Jarvelin
    •  & Paul Elliott

  21. Department of Public Health Science and General Practice, University of Oulu, Finland.

    • Marjo-Riitta Jarvelin

  22. Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, S-751 85 Uppsala, Sweden.

    • Ulf Gyllensten
    • , Åsa Johansson
    •  & Inger Jonasson

  23. Croatian Centre for Global Health, University of Split Medical School, Soltanska 2, 21000 Split, Croatia.

    • Igor Rudan

  24. Institute for Clinical Medical Research, University Hospital “Sestre Milosrdnice”, Vinogradska 29, 10000 Zagreb. CROATIA.

    • Igor Rudan

  25. Genomic Medicine, Imperial College London, South Kensington Campus, London SW7 2AZ, UK.

    • Mario Falchi

  26. Department of Internal Medicine, Erasmus University Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.

    • Eric J G Sijbrands
    •  & Andre G Uitterlinden

  27. Department of Clinical Genetics. Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.

    • Ben A Oostra

  28. Department of Biochemistry, University Hospital Oulu, 90220 Oulu, Finland.

    • Aimo Ruokonen

  29. Department of Human Genetics, UCLA School of Medicine, University of California, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA.

    • Chiara Sabatti

  30. Helmholtz-Center Munich, Institute of Human Genetics, Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany.

    • Thomas Meitinger

  31. Technical University Munich, Institute of Human Genetics, D-81675, Munich, Germany.

    • Thomas Meitinger

  32. Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Schoepfstrasse 41, A-6020 Innsbruck, Austria.

    • Florian Kronenberg

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

    • Mark I McCarthy

  34. Oxford Centre for Diabetes, Endocrinology and Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.

    • Mark I McCarthy

  35. The Broad Institute, Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.

    • Leena Peltonen

  36. Wellcome Trust Sanger Institute Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.

    • Leena Peltonen

Consortia

  1. the ENGAGE Consortium

Authors

    Contributions

    The study was designed by L.P., C.M.v.D., Y.S.A. and S.R. Genotype and phenotype information were collected by D.B., I.M.H., C.P., B.W.J.H.P., I.R., T.S., N.G.M., N.L.P., K.O.K., J.K., A.H., N.B.F., M.-R.J., U.G., H.C., J.F.W., Å.J., F.M., C.H., V.V., I.J., P.P.P., A.W., N.H., I.P., A.A.H., M.F., G.W., J.-J.H., E.J.C.d.G., G.W.M., J.W., P.M., M.P., K.S., A.I., E.J.G.S., A.G.U., J.C.M.W., B.A.O., P.E., A.R., C.S., C.G., T.M., F.K., A.D., H.-E.W., J.H.S., M.I.M., C.M.v.D. and L.P. Statistical analysis was performed by Y.S.A., S.R., I.L., A.C.J.W.J., J.-J.H. and J.S. The manuscript was written by Y.S.A., S.R., A.C.J.W.J., C.M.v.D. and L.P. All authors reviewed the manuscript.

    Corresponding author

    Correspondence to Leena Peltonen.

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    https://doi.org/10.1038/ng.269

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