Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia

Journal name:
Nature Genetics
Year published:
Published online

Genome-wide association studies (GWAS) have identified multiple loci associated with plasma lipid concentrations1, 2, 3, 4, 5. Common variants at these loci together explain <10% of variation in each lipid trait4, 5. Rare variants with large individual effects may also contribute to the heritability of lipid traits6, 7; however, the extent to which rare variants affect lipid phenotypes remains to be determined. Here we show an accumulation of rare variants, or a mutation skew, in GWAS-identified genes in individuals with hypertriglyceridemia (HTG). Through GWAS, we identified common variants in APOA5, GCKR, LPL and APOB associated with HTG. Resequencing of these genes revealed a significant burden of 154 rare missense or nonsense variants in 438 individuals with HTG, compared to 53 variants in 327 controls (P = 6.2 × 10−8), corresponding to a carrier frequency of 28.1% of affected individuals and 15.3% of controls (P = 2.6 × 10−5). Considering rare variants in these genes incrementally increased the proportion of genetic variation contributing to HTG.


  1. 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, 189197 (2008).
  2. Willer, C.J. et al. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat. Genet. 40, 161169 (2008).
  3. Sabatti, C. et al. Genome-wide association analysis of metabolic traits in a birth cohort from a founder population. Nat. Genet. 41, 3546 (2009).
  4. Aulchenko, Y.S. et al. Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat. Genet. 41, 4755 (2009).
  5. Kathiresan, S. et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat. Genet. 41, 5665 (2009).
  6. Manolio, T.A. et al. Finding the missing heritability of complex diseases. Nature 461, 747753 (2009).
  7. Kryukov, G.V., Pennacchio, L.A. & Sunyaev, S.R. Most rare missense alleles are deleterious in humans: implications for complex disease and association studies. Am. J. Hum. Genet. 80, 727739 (2007).
  8. Plomin, R., Haworth, C.M. & Davis, O.S. Common disorders are quantitative traits. Nat. Rev. Genet. 10, 872878 (2009).
  9. Wang, J. et al. Resequencing genomic DNA of patients with severe hypertriglyceridemia (MIM 144650). Arterioscler. Thromb. Vasc. Biol. 27, 24502455 (2007).
  10. Nejentsev, S. et al. Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324, 387389 (2009).
  11. Cohen, J.C. et al. Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305, 869872 (2004).
  12. Romeo, S. et al. Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL. Nat. Genet. 39, 513516 (2007).
  13. Yuan, G., Al-Shali, K.Z. & Hegele, R.A. Hypertriglyceridemia: its etiology, effects and treatment. CMAJ 176, 11131120 (2007).
  14. Hegele, R.A. et al. A polygenic basis for four classical Fredrickson hyperlipoproteinemia phenotypes that are characterized by hypertriglyceridemia. Hum. Mol. Genet. 18, 41894194 (2009).
  15. Wang, J. et al. Polygenic determinants of severe hypertriglyceridemia. Hum. Mol. Genet. 17, 28942899 (2008).
  16. Wang, J. et al. APOA5 genetic variants are markers for classic hyperlipoproteinemia phenotypes and hypertriglyceridemia. Nat. Clin. Pract. Cardiovasc. Med. 5, 730737 (2008).
  17. Hegele, R.A. Plasma lipoproteins: genetic influences and clinical implications. Nat. Rev. Genet. 10, 109121 (2009).
  18. Gaffney, D. et al. Independent mutations at codon 3500 of the apolipoprotein B gene are associated with hyperlipidemia. Arterioscler. Thromb. Vasc. Biol. 15, 10251029 (1995).
  19. Beigneux, A.P. et al. Chylomicronemia with a mutant GPIHBP1 (Q115P) that cannot bind lipoprotein lipase. Arterioscler. Thromb. Vasc. Biol. 29, 956962 (2009).
  20. Péterfy, M. et al. Mutations in LMF1 cause combined lipase deficiency and severe hypertriglyceridemia. Nat. Genet. 39, 14831487 (2007).
  21. Anand, S.S. et al. Differences in risk factors, atherosclerosis, and cardiovascular disease between ethnic groups in Canada: the Study of Health Assessment and Risk in Ethnic groups (SHARE). Lancet 356, 279284 (2000).
  22. Kathiresan, S. et al. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat. Genet. 41, 334341 (2009).
  23. Li, Y. & Abecasis, G.R. Mach 1.0: rapid haplotype reconstruction and missing genotype inference. Am. J. Hum. Genet. S79, 2290 (2006).
  24. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559575 (2007).
  25. Patterson, N., Price, A.L. & Reich, D. Population structure and eigenanalysis. PLoS Genet. 2, e190 (2006).
  26. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904909 (2006).
  27. Mittlböck, M. & Schemper, M. Computing measures of explained variation for logistic regression models. Comput. Methods Programs Biomed. 58, 1724 (1999).

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Author information


  1. Department of Biochemistry, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.

    • Christopher T Johansen,
    • Jian Wang,
    • Matthew B Lanktree,
    • Henian Cao,
    • Adam D McIntyre,
    • Matthew R Ban,
    • Rebecca A Martins,
    • Brooke A Kennedy,
    • Reina G Hassell,
    • Murray W Huff &
    • Robert A Hegele
  2. Department of Experimental Vascular Medicine, Academic Medical Center Amsterdam, Amsterdam, The Netherlands.

    • Maartje E Visser &
    • Geesje M Dallinga-Thie
  3. Department of Vascular Medicine, Academic Medical Center Amsterdam, Amsterdam, The Netherlands.

    • Maartje E Visser &
    • Geesje M Dallinga-Thie
  4. Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, USA.

    • Stephen M Schwartz
  5. Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Benjamin F Voight &
    • Sekar Kathiresan
  6. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Benjamin F Voight &
    • Sekar Kathiresan
  7. Cardiovascular Epidemiology and Genetics, Institut Municipal D'investigacio Medica, and CIBER Epidemiología y Salud Pública, Barcelona, Spain.

    • Roberto Elosua
  8. Chronic Disease Epidemiology Unit, Department of Health Promotion and Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.

    • Veikko Salomaa
  9. Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Christopher J O'Donnell
  10. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

    • Christopher J O'Donnell
  11. Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, Massachusetts, USA.

    • Christopher J O'Donnell
  12. Population Health Research Institute, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada.

    • Sonia S Anand &
    • Salim Yusuf
  13. Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.

    • Murray W Huff &
    • Robert A Hegele


Manuscript and experiment conceptualization, C.T.J. and R.A.H.; project management, C.T.J. and J.W.; GWAS and statistical analysis: C.T.J. and M.B.L.; sequencing, J.W., H.C., A.D.M., R.A.M., R.G.H. and C.T.J.; biochemical analysis, M.W.H.; clinical database management, M.R.B. and B.A.K.; study sample contributions, R.A.H., S.S.A., S.Y., M.E.V., G.M.D.-T., S.M.S., B.F.V., R.E., V.S., C.J.O. and S.K.

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The authors declare no competing financial interests.

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