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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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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

    • Sekar Kathiresan
    • , Cristen J Willer
    • , Gina M Peloso
    •  & Serkalem Demissie

    These authors contributed equally to this work.

    • Sekar Kathiresan
    • , Jose M Ordovas
    • , Michael Boehnke
    • , Gonçalo R Abecasis
    • , Karen L Mohlke
    •  & L Adrienne Cupples

    These authors contributed equally to this work.

Affiliations

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

    • Sekar Kathiresan
    •  & Kiran Musunuru
  2. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, 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, Massachusetts 02142, 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, Massachusetts 01702, 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, Massachusetts 02115, USA.

    • Sekar Kathiresan
    •  & David Altshuler
  6. Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, 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, Massachusetts 02118, USA.

    • Gina M Peloso
    • , Serkalem Demissie
    • , Qiong Yang
    • , Kathryn L Lunetta
    • , Josée Dupuis
    •  & L Adrienne Cupples
  8. Rosetta Inpharmatics LLC, Merck & Co., Inc., Seattle, Washington 98109, USA.

    • Eric E Schadt
  9. Massachusetts General Hospital Weight Center, Boston, Massachusetts 02114, 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, Maryland 21225, USA.

    • Toshiko Tanaka
    •  & Luigi Ferrucci
  12. Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Benjamin F Voight
    •  & David Altshuler
  13. National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, 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, Evry Cedex 91057, 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, California 90033, USA.

    • Richard N Bergman
  18. Diabetes Unit, Department of Health Promotion and Chronic Disease Prevention, 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, Massachusetts 02115, USA.

    • Paul I W de Bakker
  21. National, Lung, and Blood Institute, National Institutes of Health, Framingham, Massachusetts 01702, 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, 75270 Paris Cedex 06, France.

    • Pierre Meneton
  25. Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland 21224, 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, Maryland 21224, 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, Massachusetts 02115,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. Chronic Disease Epidemiology Unit, Department of Health Promotion and Chronic Disease Prevention, National Public Health Institute, Helsinki 00300, Finland.

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

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

    • Jose M Ordovas
  36. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, 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 or Gonçalo R Abecasis or Karen L Mohlke or L Adrienne Cupples.

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https://doi.org/10.1038/ng.291

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