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Common variants at 30 loci contribute to polygenic dyslipidemia

Nature Genetics volume 41, pages 56–65 (2009)Cite this article

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Abstract

Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to 20,623 individuals. We identified 30 distinct loci associated with lipoprotein concentrations (each with P < 5 × 10−8), including 11 loci that reached genome-wide significance for the first time. The 11 newly defined loci include common variants associated with LDL cholesterol near ABCG8, MAFB, HNF1A and TIMD4; with HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B; and with triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to an allelic dosage score (P < 10−15 for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.

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Figure 1: Summary of genome-wide association results for LDL cholesterol, HDL cholesterol and triglycerides from stage 1.
Figure 2: Regional plots of 11 confirmed associations.
Figure 3: Mean lipoprotein concentrations and proportion of individuals with low HDL cholesterol, high LDL cholesterol or high triglycerides, as a function of allelic dosage score for HDL cholesterol, LDL cholesterol and triglycerides, respectively.

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Change history

  • 14 December 2008

    NOTE: In the version of this article initially published online, Paul I.W. de Bakker?s name was misspelled in the author list. The error has been corrected for all versions of this article.

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Acknowledgements

The FHS authors thank the FHS participants for their long-term voluntary commitment to this study. The FHS is supported by a contract from the National Heart, Lung and Blood Institute (NHLBI; contract no. N01-HC-25195). The NHLBI's SNP Health Association Resource research program supported the FHS genotyping. J.M.O. is supported by NHLBI grant HL-54776 and by contracts 53-K06-5-10 and 58-1950-9-001 from the US Department of Agriculture Research Service.

The DGI and MDC-CC authors thank R. Saxena, V. Lyssenko, M. Daly, J. Hirschhorn, S. Gabriel, H. Chen, T. Hughes, the entire DGI study team and the Botnia Study team for their roles in sample collection, phenotyping, design and conduct of the DGI study; and M. Svenson and L. Rosberg for technical assistance in Malmö. S.K. is supported by a Doris Duke Charitable Foundation Clinical Scientist Development Award, a charitable gift from the Fannie E. Rippel Foundation, the Donovan Family Foundation, a career development award from the United States National Institutes of Health (NIH) and institutional support from the Department of Medicine and Cardiovascular Research Center at Massachusetts General Hospital. L.G. is supported by the Sigrid Juselius Foundation, the Finnish Diabetes Research Foundation, The Folkhalsan Research Foundation and Clinical Research Institute HUCH Ltd. His work in Malmö, Sweden, was also funded by a Linné grant from the Swedish Medical Research Council. M.O.-M. is supported by a European Foundation for the Study of Diabetes–Pfizer grant and the Novo Nordisk Foundation. M.O.-M. and O.M. are supported by the Swedish Medical Research Council, the Swedish Heart and Lung Foundation, the Medical Faculty of Lund University, Malmö University Hospital, the Albert Påhlsson Research Foundation and the Crafoord Foundation. O.M. is also supported by the Swedish Medical Society, the Ernhold Lundströms Research Foundation, the Mossfelt Foundation, the King Gustav V and Queen Victoria Foundation and the Region Skane.

The FUSION and METSIM authors thank the Finnish citizens who generously participated in these studies. Support for FUSION was provided by NIH grants DK062370 (to M.B.) and DK072193 (to K.L.M.), intramural project number 1Z01 HG000024 (to F.S.C.) and a postdoctoral fellowship award from the American Diabetes Association (to C.J.W.). K.L.M. is a Pew Scholar for the Biomedical Sciences. Genome-wide genotyping was conducted by the Johns Hopkins University Genetic Resources Core Facility SNP Center at the Center for Inherited Disease Research (CIDR), with support from CIDR NIH contract no. N01-HG-65403. Support for METSIM was provided by grant 124243 from the Academy of Finland (to M.L.).

The SardiNIA authors thank the many volunteers who generously participated in these studies. This work was supported in part by the Intramural Research Program of the National Institute on Aging and by extramural grants from the National Human Genome Research Institute (HG02651) and the NHLBI (HL084729). Additional support was provided by the mayors, administrations and residents of Lanusei, Ilbono, Arzana and Elini and the head of Public Health Unit ASL4 in Sardinia. G.R.A. is a Pew Scholar for the Biomedical Sciences.

FINRISK97 author L.P. is supported by the Center of Excellence in Complex Disease Genetics of the Academy of Finland and the Nordic Center of Excellence in Disease Genetics. V.S. was supported by the Sigrid Juselius Foundation and the Finnish Foundation for Cardiovascular Research.

The ISIS trials and epidemiological studies were supported by the manufacturers of the study drugs and by the British Heart Foundation, Medical Research Council, Cancer Research UK, Tobacco Products Research Trust of the UK Department of Health Independent Scientific Committee on Smoking and Health, and the Oxford Genetics Knowledge Park.

Author information

Author notes

  1. Sekar Kathiresan, Cristen J Willer, Gina M Peloso and Serkalem Demissie: These authors contributed equally to this work.

  2. Sekar Kathiresan, Jose M Ordovas, Michael Boehnke, Gonçalo R Abecasis, Karen L Mohlke and L Adrienne Cupples: These authors contributed equally to this work.

Authors and Affiliations

  1. Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, 02114, Massachusetts, USA

    Sekar Kathiresan & Kiran Musunuru

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

    Sekar Kathiresan, Kiran Musunuru & Benjamin F Voight

  3. Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, 02142, Massachusetts, USA

    Sekar Kathiresan, Benjamin F Voight, Gabriel Crawford, Aarti Surti, Candace Guiducci, Noel P Burtt, David Altshuler & Leena Peltonen

  4. Framingham Heart Study of the National, Heart, Lung, and Blood Institute and Boston University, Framingham, 01702, Massachusetts, USA

    Sekar Kathiresan, Gina M Peloso, Serkalem Demissie, Qiong Yang, Kathryn L Lunetta, Josée Dupuis, Christopher J O'Donnell & L Adrienne Cupples

  5. Department of Medicine, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Sekar Kathiresan & David Altshuler

  6. Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, 48109, Michigan, USA

    Cristen J Willer, Yun Li, Anne U Jackson, Laura J Scott, Heather M Stringham, Paul Scheet, Michael Boehnke & Gonçalo R Abecasis

  7. Department of Biostatistics, Boston University School of Public Health, Boston, 02118, Massachusetts, USA

    Gina M Peloso, Serkalem Demissie, Qiong Yang, Kathryn L Lunetta, Josée Dupuis & L Adrienne Cupples

  8. Rosetta Inpharmatics LLC, Merck & Co., Inc., Seattle, 98109, Washington, USA

    Eric E Schadt

  9. Massachusetts General Hospital Weight Center, Boston, 02114, Massachusetts, USA

    Lee Kaplan

  10. Clinical Trial Service Unit, University of Oxford, Oxford, OX3 7LF, UK

    Derrick Bennett, Sarah Parish, Robert Clarke & Rory Collins

  11. Clinical Research Branch, National Institute on Aging, National Institutes of Health, Baltimore, 21225, Maryland, USA

    Toshiko Tanaka & Luigi Ferrucci

  12. Department of Molecular Biology, Massachusetts General Hospital, Boston, 02114, Massachusetts, USA

    Benjamin F Voight & David Altshuler

  13. National Human Genome Research Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Lori L Bonnycastle, Kari A Kubalanza, Mario A Morken, Amy J Swift & Francis S Collins

  14. Centre Nationale de Genotypage, Institut Genomique, Commissariat a l'Energie Atomique, 91057, Evry Cedex, France

    Diana Zelenika & G Mark Lathrop

  15. INSERM U557, INRA U1125, CNAM, Paris 13 SMBH, Bobigny, France

    Pilar Galan & Serge Hercberg

  16. Department of Medicine, University of Kuopio, Kuopio, 70210, Finland

    Johanna Kuusisto & Markku Laakso

  17. Department of Physiology and Biophysics, University of Southern California Keck School of Medicine, Los Angeles, 90033, California, USA

    Richard N Bergman

  18. Department of Health Promotion and Chronic Disease Prevention, Diabetes Unit, National Public Health Institute, Helsinki, 00300, Finland

    Jouko Sundvall & Jaakko Tuomilehto

  19. Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cagliari, 08045, Italy

    Serena Sanna & Manuela Uda

  20. Division of Genetics, Bringham and Women's Hospital, Boston, 02115, Massachusetts, USA

    Paul I W de Bakker

  21. National, Lung, and Blood Institute, National Institutes of Health, Framingham, 01702, Massachusetts, USA

    Christopher J O'Donnell

  22. Department of Epidemiology and Public Health, Imperial College London, London, W2 1PG, UK

    John C Chambers

  23. Hammersmith Hospital, National Heart and Lung Institute, Imperial College London, London, W12 0NN, UK

    Jaspal S Kooner

  24. INSERM U872, Centre de Recherche des Cordeliers, Paris, 75270, Cedex 06, France

    Pierre Meneton

  25. Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, Baltimore, 21224, Maryland, USA

    Edward G Lakatta

  26. Unità Operativa Geriatria, Istituto Nazionale Ricovero e Cura per Anziani, 00189, Rome, Italy

    Angelo Scuteri

  27. Laboratory of Genetics, Gerontology Research Center, National Institute on Aging, Baltimore, 21224, Maryland, USA

    David Schlessinger

  28. Department of Clinical Sciences, Diabetes and Endocrinology, University Hospital Malmö, Lund University, Malmö, 20502, Sweden

    Leif Groop & Marju Orho-Melander

  29. Department of Medicine, Helsinki University Hospital, Helsinki, 00029, Finland

    Leif Groop

  30. Department of Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA

    David Altshuler

  31. Department of Clinical Sciences, Hypertension and Cardiovascular Diseases, University Hospital Malmö, Lund University, Malmö, 20502, Sweden

    Olle Melander

  32. Institute for Molecular Medicine, University of Helsinki, Helsinki, 00029, Finland

    Leena Peltonen

  33. Department of Health Promotion and Chronic Disease Prevention, Chronic Disease Epidemiology Unit, National Public Health Institute, Helsinki, 00300, Finland

    Veikko Salomaa

  34. Wellcome Trust Sanger Institute, CB10 1SA, Cambridge, UK

    Leena Peltonen

  35. Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Nutrition and Genomics Laboratory, Boston, 02111, Massachusetts, USA

    Jose M Ordovas

  36. Department of Genetics, University of North Carolina, Chapel Hill, 27599, North Carolina, USA

    Karen L Mohlke

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Contributions

Writing team and project management: S.K., C.J.W., G.M.P., S.D., M.O.-M., J.M.O., M.B., G.R.A., K.L.M. and L.A.C. Study design: S.K., J.M.O., C.J.O., L.A.C., J.C.C., J.S.K., P.M., S.H., L.F., D.A., L.G., R.N.B., J.T., F.S.C., M.B., K.L.M., E.G.L., A.S., M.U., D.S., G.R.A., M.O.-M., O.M., V.S., L.P., G.M.L., R. Collins and E.E.S. Clinical samples, phenotyping and genotyping: J.M.O., L.L.B., K.A.K., M.A.M., L.A.C., P.G., A.J.S., J.K., R.N.B., J.S., M.L., L.F., S.H., P.M., G.M.L., M.O.-M., O.M., S.K., G.C., A.S., C.G., N.P.B. and L.K. Data analysis: S.K., C.J.W., G.M.P., S.D., K.M., D.B., Y.L., T.T., B.F.V., A.U.J., S.P., R. Clarke, D.Z., L.J.S., H.M.S., P.S., S.S., M.U., Q.Y., K.L.L., J.D., P.I.W.d.B., J.C.C., E.E.S. and G.R.A.

Corresponding authors

Correspondence to Sekar Kathiresan, Gonçalo R Abecasis, Karen L Mohlke or L Adrienne Cupples.

Supplementary information

Supplementary Text and Figures

Supplementary Methods, Supplementary Figures 1–3 and Supplementary Tables 1–7 (PDF 1392 kb)

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Kathiresan, S., Willer, C., Peloso, G. et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet 41, 56–65 (2009). https://doi.org/10.1038/ng.291

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