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


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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Figure 1: Rare variants identified by resequencing GWAS-identified genes in individuals with HTG and controls.

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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



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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Correspondence to Robert A Hegele.

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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).

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