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 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.
Johansen
Christopher T
CT
Department of Biochemistry, University of Western Ontario, London, Ontario, Canada.
Wang
Jian
J
Lanktree
Matthew B
MB
Cao
Henian
H
McIntyre
Adam D
AD
Ban
Matthew R
MR
Martins
Rebecca A
RA
Kennedy
Brooke A
BA
Hassell
Reina G
RG
Visser
Maartje E
ME
Schwartz
Stephen M
SM
Voight
Benjamin F
BF
Elosua
Roberto
R
Salomaa
Veikko
V
O'Donnell
Christopher J
CJ
Dallinga-Thie
Geesje M
GM
Anand
Sonia S
SS
Yusuf
Salim
S
Huff
Murray W
MW
Kathiresan
Sekar
S
Hegele
Robert A
RA
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
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