Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia (original) (raw)

References

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, 189–197 (2008).
   Article CAS Google Scholar
2. 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
3. Sabatti, C. et al. Genome-wide association analysis of metabolic traits in a birth cohort from a founder population. Nat. Genet. 41, 35–46 (2009).
   Article CAS Google Scholar
4. Aulchenko, Y.S. et al. Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat. Genet. 41, 47–55 (2009).
   Article CAS Google Scholar
5. Kathiresan, S. et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat. Genet. 41, 56–65 (2009).
   Article CAS Google Scholar
6. Manolio, T.A. et al. Finding the missing heritability of complex diseases. Nature 461, 747–753 (2009).
   Article CAS Google Scholar
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, 727–739 (2007).
   Article CAS Google Scholar
8. Plomin, R., Haworth, C.M. & Davis, O.S. Common disorders are quantitative traits. Nat. Rev. Genet. 10, 872–878 (2009).
   Article CAS Google Scholar
9. Wang, J. et al. Resequencing genomic DNA of patients with severe hypertriglyceridemia (MIM 144650). Arterioscler. Thromb. Vasc. Biol. 27, 2450–2455 (2007).
   Article CAS Google Scholar
10. Nejentsev, S. et al. Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324, 387–389 (2009).
    Article CAS Google Scholar
11. Cohen, J.C. et al. Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305, 869–872 (2004).
    Article CAS Google Scholar
12. 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
13. Yuan, G., Al-Shali, K.Z. & Hegele, R.A. Hypertriglyceridemia: its etiology, effects and treatment. CMAJ 176, 1113–1120 (2007).
    Article Google Scholar
14. Hegele, R.A. et al. A polygenic basis for four classical Fredrickson hyperlipoproteinemia phenotypes that are characterized by hypertriglyceridemia. Hum. Mol. Genet. 18, 4189–4194 (2009).
    Article CAS Google Scholar
15. Wang, J. et al. Polygenic determinants of severe hypertriglyceridemia. Hum. Mol. Genet. 17, 2894–2899 (2008).
    Article CAS Google Scholar
16. Wang, J. et al. APOA5 genetic variants are markers for classic hyperlipoproteinemia phenotypes and hypertriglyceridemia. Nat. Clin. Pract. Cardiovasc. Med. 5, 730–737 (2008).
    Article CAS Google Scholar
17. Hegele, R.A. Plasma lipoproteins: genetic influences and clinical implications. Nat. Rev. Genet. 10, 109–121 (2009).
    Article CAS Google Scholar
18. Gaffney, D. et al. Independent mutations at codon 3500 of the apolipoprotein B gene are associated with hyperlipidemia. Arterioscler. Thromb. Vasc. Biol. 15, 1025–1029 (1995).
    Article CAS Google Scholar
19. Beigneux, A.P. et al. Chylomicronemia with a mutant GPIHBP1 (Q115P) that cannot bind lipoprotein lipase. Arterioscler. Thromb. Vasc. Biol. 29, 956–962 (2009).
    Article CAS Google Scholar
20. Péterfy, M. et al. Mutations in LMF1 cause combined lipase deficiency and severe hypertriglyceridemia. Nat. Genet. 39, 1483–1487 (2007).
    Article Google Scholar
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, 279–284 (2000).
    Article CAS Google Scholar
22. Kathiresan, S. et al. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat. Genet. 41, 334–341 (2009).
    Article CAS Google Scholar
23. Li, Y. & Abecasis, G.R. Mach 1.0: rapid haplotype reconstruction and missing genotype inference. Am. J. Hum. Genet. S79, 2290 (2006).
    Google Scholar
24. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).
    Article CAS Google Scholar
25. Patterson, N., Price, A.L. & Reich, D. Population structure and eigenanalysis. PLoS Genet. 2, e190 (2006).
    Article Google Scholar
26. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).
    Article CAS Google Scholar
27. Mittlböck, M. & Schemper, M. Computing measures of explained variation for logistic regression models. Comput. Methods Programs Biomed. 58, 17–24 (1999).
    Article Google Scholar

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Acknowledgements

We thank the London Regional Genomics Centre (D. Carter, G. Barbe and K. Kang) for their dedication to this project, and the Myocardial Infarction Genetics Consortium (MIGen) study for the use of their genotype data as control data in our study. The MIGen study was funded by the US National Institutes of Health through the National Heart, Lung, and Blood Institute's STAMPEED genomics research program (R01 HL087676) and the National Center for Research Resources (U54 RR020278). This work was made possible by the facilities of the Shared Hierarchical Academic Research Computing Network (SHARCNET). C.T.J. is supported by a Canadian Institutes of Health Research (CIHR) Banting and Best Canada Graduate Scholarship, a Heart and Stroke Foundation of Ontario Program Grant and a CIHR Vascular Research Fellowship. V.S. was supported by the Sigrid Juselius Foundation and by the Finnish Academy (grant 129494). S.S.A. is supported by the Michael G. DeGroote Heart and Stroke Foundation of Ontario Chair and the Eli Lilly May Cohen Chair in Women's Health Research at McMaster University. R.A.H. is supported by the Jacob J. Wolfe Distinguished Medical Research Chair, the Edith Schulich Vinet Canada Research Chair in Human Genetics (Tier I), the Martha G. Blackburn Chair in Cardiovascular Research and operating grants from the CIHR (MOP-13430, MOP-79523, CTP-79853), the Heart and Stroke Foundation of Ontario (NA-6059, T-6018, PRG-4854), the Pfizer Jean Davignon Distinguished Cardiovascular and Metabolic Research Award and Genome Canada through the Ontario Genomics Institute.

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Authors and 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. Department of Health Promotion and Chronic Disease Prevention, Chronic Disease Epidemiology Unit, 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

Authors

1. Christopher T Johansen
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2. Jian Wang
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3. Matthew B Lanktree
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4. Henian Cao
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5. Adam D McIntyre
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6. Matthew R Ban
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7. Rebecca A Martins
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8. Brooke A Kennedy
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9. Reina G Hassell
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10. Maartje E Visser
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11. Stephen M Schwartz
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12. Benjamin F Voight
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13. Roberto Elosua
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14. Veikko Salomaa
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15. Christopher J O'Donnell
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16. Geesje M Dallinga-Thie
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17. Sonia S Anand
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18. Salim Yusuf
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19. Murray W Huff
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20. Sekar Kathiresan
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21. Robert A Hegele
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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.

Corresponding author

Correspondence toRobert A Hegele.

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The authors declare no competing financial interests.

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Johansen, C., Wang, J., Lanktree, M. et al. Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia.Nat Genet 42, 684–687 (2010). https://doi.org/10.1038/ng.628

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• Received: 01 April 2010
• Accepted: 22 June 2010
• Published: 25 July 2010
• Issue Date: August 2010
• DOI: https://doi.org/10.1038/ng.628