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

Journal name:
Nature Genetics
Volume:
42,
Pages:
684–687
Year published:
DOI:
doi:10.1038/ng.628
Received
Accepted
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.

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Author information

Affiliations

  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

Contributions

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.

Competing financial interests

The authors declare no competing financial interests.

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