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- Title
Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia.
- Authors
Johansen, Christopher T; Wang, Jian; Lanktree, Matthew B; Cao, Henian; McIntyre, Adam D; Ban, Matthew R; Martins, Rebecca A; Kennedy, Brooke A; Hassell, Reina G; Visser, Maartje E; Schwartz, Stephen M; Voight, Benjamin F; Elosua, Roberto; Salomaa, Veikko; O'Donnell, Christopher J; Dallinga-Thie, Geesje M; Anand, Sonia S; Yusuf, Salim; Huff, Murray W; Kathiresan, Sekar; Hegele, Robert A
- Abstract
Genome-wide association studies (GWAS) have identified multiple loci associated with plasma lipid concentrations. Common variants at these loci together explain <10% of variation in each lipid trait. Rare variants with large individual effects may also contribute to the heritability of lipid traits; 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 x 10(-8)), corresponding to a carrier frequency of 28.1% of affected individuals and 15.3% of controls (P = 2.6 x 10(-5)). Considering rare variants in these genes incrementally increased the proportion of genetic variation contributing to HTG.
- Publication
Nature genetics, 2010, Vol 42, Issue 8, p684
- ISSN
1546-1718
- Publication type
Journal Article
- DOI
10.1038/ng.628