Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Common variants at 30 loci contribute to polygenic dyslipidemia

This article has been updated

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

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.

References

  1. Manolio, T.A., Brooks, L.D. & Collins, F.S.A. HapMap harvest of insights into the genetics of common disease. J. Clin. Invest. 118, 1590–1605 (2008).

    Article  CAS  Google Scholar 

  2. Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316, 1331–1336 (2007).

  3. Kathiresan, S. et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat. Genet. 40, 189–197 (2008).

    Article  CAS  Google Scholar 

  4. Willer, C.J. et al. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat. Genet. 40, 161–169 (2008).

    Article  CAS  Google Scholar 

  5. Wallace, C. et al. Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia. Am. J. Hum. Genet. 82, 139–149 (2008).

    Article  CAS  Google Scholar 

  6. Sandhu, M.S. et al. LDL-cholesterol concentrations: a genome-wide association study. Lancet 371, 483–491 (2008).

    Article  CAS  Google Scholar 

  7. Kannel, W.B., Dawber, T.R., Kagan, A., Revotskie, N. & Stokes, J. III. Factors of risk in the development of coronary heart disease–six year follow-up experience. The Framingham Study. Ann. Intern. Med. 55, 33–50 (1961).

    Article  CAS  Google Scholar 

  8. Kannel, W.B., Feinleib, M., McNamara, P.M., Garrison, R.J. & Castelli, W.P. An investigation of coronary heart disease in families. The Framingham offspring study. Am. J. Epidemiol. 110, 281–290 (1979).

    Article  CAS  Google Scholar 

  9. Splansky, G.L. et al. The Third Generation Cohort of the National Heart, Lung, and Blood Institute's Framingham Heart Study: design, recruitment, and initial examination. Am. J. Epidemiol. 165, 1328–1335 (2007).

    Article  Google Scholar 

  10. Pe'er, I., Yelensky, R., Altshuler, D. & Daly, M.J. Estimation of the multiple testing burden for genomewide association studies of nearly all common variants. Genet. Epidemiol. 32, 381–385 (2008).

    Article  Google Scholar 

  11. Berglund, G., Elmstahl, S., Janzon, L. & Larsson, S.A. The Malmo Diet and Cancer Study. Design and feasibility. J. Intern. Med. 233, 45–51 (1993).

    Article  CAS  Google Scholar 

  12. Vartiainen, E. et al. Cardiovascular risk factor changes in Finland, 1972–1997. Int. J. Epidemiol. 29, 49–56 (2000).

    Article  CAS  Google Scholar 

  13. Scott, L.J. et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316, 1341–1345 (2007).

    Article  CAS  Google Scholar 

  14. ISIS-3. A randomised comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41,299 cases of suspected acute myocardial infarction. ISIS-3 (Third International Study of Infarct Survival) Collaborative Group. Lancet 339, 753–770 (1992).

  15. Kajinami, K., Brousseau, M.E., Nartsupha, C., Ordovas, J.M. & Schaefer, E.J. ATP binding cassette transporter G5 and G8 genotypes and plasma lipoprotein levels before and after treatment with atorvastatin. J. Lipid Res. 45, 653–656 (2004).

    Article  CAS  Google Scholar 

  16. Romeo, S. et al. Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL. Nat. Genet. 39, 513–516 (2007).

    Article  CAS  Google Scholar 

  17. Schaeffer, L. et al. Common genetic variants of the FADS1 FADS2 gene cluster and their reconstructed haplotypes are associated with the fatty acid composition in phospholipids. Hum. Mol. Genet. 15, 1745–1756 (2006).

    Article  CAS  Google Scholar 

  18. Ek, J. et al. The functional Thr130Ile and Val255Met polymorphisms of the hepatocyte nuclear factor-4alpha (HNF4A): gene associations with type 2 diabetes or altered beta-cell function among Danes. J. Clin. Endocrinol. Metab. 90, 3054–3059 (2005).

    Article  CAS  Google Scholar 

  19. Pare, G. et al. Genetic analysis of 103 candidate genes for coronary artery disease and associated phenotypes in a founder population reveals a new association between endothelin-1 and high-density lipoprotein cholesterol. Am. J. Hum. Genet. 80, 673–682 (2007).

    Article  CAS  Google Scholar 

  20. Spirin, V. et al. Common single-nucleotide polymorphisms act in concert to affect plasma levels of high-density lipoprotein cholesterol. Am. J. Hum. Genet. 81, 1298–1303 (2007).

    Article  CAS  Google Scholar 

  21. Hegele, R.A. et al. The private hepatocyte nuclear factor-1alpha G319S variant is associated with plasma lipoprotein variation in Canadian Oji-Cree. Arterioscler. Thromb. Vasc. Biol. 20, 217–222 (2000).

    Article  CAS  Google Scholar 

  22. Schadt, E.E. et al. Mapping the genetic architecture of gene expression in human liver. PLoS Biol. 6, e107 (2008).

    Article  Google Scholar 

  23. Jiang, X. et al. Increased prebeta-high density lipoprotein, apolipoprotein AI, and phospholipid in mice expressing the human phospholipid transfer protein and human apolipoprotein AI transgenes. J. Clin. Invest. 98, 2373–2380 (1996).

    Article  CAS  Google Scholar 

  24. Jiang, X.C. et al. Targeted mutation of plasma phospholipid transfer protein gene markedly reduces high-density lipoprotein levels. J. Clin. Invest. 103, 907–914 (1999).

    Article  CAS  Google Scholar 

  25. Isaacs, A., Sayed-Tabatabaei, F.A., Njajou, O.T., Witteman, J.C. & van Duijn, C.M. The -514 C-&gt;T hepatic lipase promoter region polymorphism and plasma lipids: a meta-analysis. J. Clin. Endocrinol. Metab. 89, 3858–3863 (2004).

    Article  CAS  Google Scholar 

  26. Phillipson, B.E., Rothrock, D.W., Connor, W.E., Harris, W.S. & Illingworth, D.R. Reduction of plasma lipids, lipoproteins, and apoproteins by dietary fish oils in patients with hypertriglyceridemia. N. Engl. J. Med. 312, 1210–1216 (1985).

    Article  CAS  Google Scholar 

  27. Blatch, G.L. & Lassle, M. The tetratricopeptide repeat: a structural motif mediating protein-protein interactions. Bioessays 21, 932–939 (1999).

    Article  CAS  Google Scholar 

  28. Berge, K.E. et al. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 290, 1771–1775 (2000).

    Article  CAS  Google Scholar 

  29. Funke, H. et al. A molecular defect causing fish eye disease: an amino acid exchange in lecithin-cholesterol acyltransferase (LCAT) leads to the selective loss of alpha-LCAT activity. Proc. Natl. Acad. Sci. USA 88, 4855–4859 (1991).

    Article  CAS  Google Scholar 

  30. Buch, S. et al. A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease. Nat. Genet. 39, 995–999 (2007).

    Article  CAS  Google Scholar 

  31. Odom, D.T. et al. Control of pancreas and liver gene expression by HNF transcription factors. Science 303, 1378–1381 (2004).

    Article  CAS  Google Scholar 

  32. Hayhurst, G.P., Lee, Y.H., Lambert, G., Ward, J.M. & Gonzalez, F.J. Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol. Cell. Biol. 21, 1393–1403 (2001).

    Article  CAS  Google Scholar 

  33. Shih, D.Q. et al. Hepatocyte nuclear factor-1alpha is an essential regulator of bile acid and plasma cholesterol metabolism. Nat. Genet. 27, 375–382 (2001).

    Article  CAS  Google Scholar 

  34. Yoshida, K., Shimizugawa, T., Ono, M. & Furukawa, H. Angiopoietin-like protein 4 is a potent hyperlipidemia-inducing factor in mice and inhibitor of lipoprotein lipase. J. Lipid Res. 43, 1770–1772 (2002).

    Article  CAS  Google Scholar 

  35. Toomey, R.E. & Wakil, S.J. Studies on the mechanism of fatty acid synthesis. XVI. Preparation and general properties of acyl-malonyl acyl carrier protein-condensing enzyme from Escherichia coli. J. Biol. Chem. 241, 1159–1165 (1966).

    CAS  PubMed  Google Scholar 

  36. Miyanishi, M. et al. Identification of Tim4 as a phosphatidylserine receptor. Nature 450, 435–439 (2007).

    Article  CAS  Google Scholar 

  37. Petersen, H.H. et al. Low-density lipoprotein receptor-related protein interacts with MafB, a regulator of hindbrain development. FEBS Lett. 565, 23–27 (2004).

    Article  CAS  Google Scholar 

  38. Aalto-Setala, K. et al. Mechanism of hypertriglyceridemia in human apolipoprotein (apo) CIII transgenic mice. Diminished very low density lipoprotein fractional catabolic rate associated with increased apo CIII and reduced apo E on the particles. J. Clin. Invest. 90, 1889–1900 (1992).

    Article  CAS  Google Scholar 

  39. Luke, M.M. et al. A polymorphism in the protease-like domain of apolipoprotein(a) is associated with severe coronary artery disease. Arterioscler. Thromb. Vasc. Biol. 27, 2030–2036 (2007).

    Article  CAS  Google Scholar 

  40. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 285, 2486–2497 (2001).

  41. Cohen, J. et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat. Genet. 37, 161–165 (2005).

    Article  CAS  Google Scholar 

  42. Abifadel, M. et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet. 34, 154–156 (2003).

    Article  CAS  Google Scholar 

  43. Kotowski, I.K. et al. A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am. J. Hum. Genet. 78, 410–422 (2006).

    Article  CAS  Google Scholar 

  44. Maxwell, K.N., Fisher, E.A. & Breslow, J.L. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proc. Natl. Acad. Sci. USA 102, 2069–2074 (2005).

    Article  CAS  Google Scholar 

  45. Park, S.W., Moon, Y.A. & Horton, J.D. Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J. Biol. Chem. 279, 50630–50638 (2004).

    Article  CAS  Google Scholar 

  46. Benjannet, S. et al. NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol. J. Biol. Chem. 279, 48865–48875 (2004).

    Article  CAS  Google Scholar 

  47. Cohen, J.C., Boerwinkle, E., Mosley, T.H. Jr & Hobbs, H.H. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med. 354, 1264–1272 (2006).

    Article  CAS  Google Scholar 

  48. Kathiresan, S. et al. Polymorphisms associated with cholesterol and risk of cardiovascular events. N. Engl. J. Med. 358, 1240–1249 (2008).

    Article  CAS  Google Scholar 

  49. Kathiresan, S. et al. A genome-wide association study for blood lipid phenotypes in the Framingham Heart Study. BMC Med. Genet. 8 Suppl 1, S17 (2007).

    Article  Google Scholar 

  50. Lange, K. & Boehnke, M. Extensions to pedigree analysis. IV. Covariance components models for multivariate traits. Am. J. Med. Genet. 14, 513–524 (1983).

    Article  CAS  Google Scholar 

Download references

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

Authors and Affiliations

Authors

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)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing