title: Excess of rare variants in non-genome-wide association study candidate genes in patients with hypertriglyceridemia.
abstract: BACKGROUND
  Rare variant accumulation studies can implicate genes in disease susceptibility when a significant burden is observed in patients versus control subjects. Such analyses might be particularly useful for candidate genes that are selected based on experiments other than genome-wide association studies (GWAS). We sought to determine whether rare variants in non-GWAS candidate genes identified from mouse models and human mendelian syndromes of hypertriglyceridemia (HTG) accumulate in patients with polygenic adult-onset HTG.
  
  
  RESULTS
  We resequenced protein coding regions of 3 genes with established roles (APOC2, GPIHBP1, LMF1) and 2 genes recently implicated (CREB3L3 and ZHX3) in TG metabolism. We identified 41 distinct heterozygous rare variants, including 29 singleton variants, in the combined sample; in total, we observed 47 rare variants in 413 HTG patients versus 16 in 324 control subjects (odds ratio=2.3; P=0.0050). Post hoc assessment of genetic burden in individual genes using 3 different tests suggested that the genetic burden was most prominent in the established genes LMF1 and APOC2, and also in the recently identified CREB3L3 gene.
  
  
  CONCLUSIONS
  These extensive resequencing studies show a significant accumulation of rare genetic variants in non-GWAS candidate genes among patients with polygenic HTG, and indicate the importance of testing specific hypotheses in large-scale resequencing studies.
authors.affiliation: Department of Biochemistry, Robarts Research Institute, University of Western Ontario, London, ON, Canada.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Johansen
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Adam D
authors.initials: AD
authors.lastname: McIntyre
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Martins
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Ban
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Lanktree
authors.forename: Murray W
authors.initials: MW
authors.lastname: Huff
authors.forename: Miklós
authors.initials: M
authors.lastname: Péterfy
authors.forename: Margarete
authors.initials: M
authors.lastname: Mehrabian
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
authors.forename: Sonia S
authors.initials: SS
authors.lastname: Anand
authors.forename: Salim
authors.initials: S
authors.lastname: Yusuf
authors.forename: Ann-Hwee
authors.initials: AH
authors.lastname: Lee
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Glimcher
authors.forename: Henian
authors.initials: H
authors.lastname: Cao
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
mesh_terms: D000328:Adult; D000368:Aged; D053304:Apolipoprotein C-II / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D015331:Cohort Studies; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D015228:Hypertriglyceridemia / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D016017:Odds Ratio; D018110:Receptors, Lipoprotein; D012097:Repressor Proteins / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: D053304:Apolipoprotein C-II; C533813:CREB3L3 protein, human; D002352:Carrier Proteins; D017362:Cyclic AMP Response Element-Binding Protein; C523701:GPIHBP1 protein, human; D018398:Homeodomain Proteins; C546366:LMF1 protein, human; D008565:Membrane Proteins; D018110:Receptors, Lipoprotein; D012097:Repressor Proteins; C476878:ZHX3 protein, human