title: Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia.
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.
authors.affiliation: Department of Biochemistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Johansen
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Lanktree
authors.forename: Henian
authors.initials: H
authors.lastname: Cao
authors.forename: Adam D
authors.initials: AD
authors.lastname: McIntyre
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Ban
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Martins
authors.forename: Brooke A
authors.initials: BA
authors.lastname: Kennedy
authors.forename: Reina G
authors.initials: RG
authors.lastname: Hassell
authors.forename: Maartje E
authors.initials: ME
authors.lastname: Visser
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Schwartz
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Voight
authors.forename: Roberto
authors.initials: R
authors.lastname: Elosua
authors.forename: Veikko
authors.initials: V
authors.lastname: Salomaa
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.forename: Geesje M
authors.initials: GM
authors.lastname: Dallinga-Thie
authors.forename: Sonia S
authors.initials: SS
authors.lastname: Anand
authors.forename: Salim
authors.initials: S
authors.lastname: Yusuf
authors.forename: Murray W
authors.initials: MW
authors.lastname: Huff
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000072040:Apolipoprotein A-V; D001054:Apolipoproteins A; D015331:Cohort Studies; D005260:Female; D005796:Genes; D005820:Genetic Testing; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D015228:Hypertriglyceridemia / Q000235:genetics*; D008055:Lipids / Q000097:blood* / Q000235:genetics*; D008071:Lipoprotein Lipase; D008297:Male; D008875:Middle Aged; D010641:Phenotype
chemical_list: C437704:APOA5 protein, human; D048868:Adaptor Proteins, Signal Transducing; D000072040:Apolipoprotein A-V; D001054:Apolipoproteins A; C485100:GCKR protein, human; D008055:Lipids; D008071:Lipoprotein Lipase