title: Exome sequencing identifies 2 rare variants for low high-density lipoprotein cholesterol in an extended family.
abstract: BACKGROUND
  Exome sequencing is a recently implemented method to discover rare mutations for Mendelian disorders. Less is known about its feasibility to identify genes for complex traits. We used exome sequencing to search for rare variants responsible for a complex trait, low levels of serum high-density lipoprotein cholesterol (HDL-C).
  
  
  RESULTS
  We conducted exome sequencing in a large French-Canadian family with 75 subjects available for study, of which 27 had HDL-C values less than the fifth age-sex-specific population percentile. We captured ≈50 Mb of exonic and transcribed sequences of 3 closely related family members with HDL-C levels less than the fifth age-sex percentile and sequenced the captured DNA. Approximately 82,000 variants were detected in each individual, of which 41 rare nonsynonymous variants were shared by the sequenced affected individuals after filtering steps. Two rare nonsynonymous variants in the ATP-binding cassette, subfamily A (ABC1), member 1 (ABCA1), and lipoprotein lipase genes predicted to be damaging were investigated for cosegregation with the low HDL-C trait in the entire extended family. The carriers of either variant had low HDL-C levels, and the individuals carrying both variants had the lowest HDL-C values. Interestingly, the ABCA1 variant exhibited a sex effect which was first functionally identified, and, subsequently, statistically demonstrated using additional French-Canadian families with ABCA1 mutations.
  
  
  CONCLUSIONS
  This complex combination of 2 rare variants causing low HDL-C in the extended family would not have been identified using traditional linkage analysis, emphasizing the need for exome sequencing of complex lipid traits in unexplained familial cases.
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: M V Prasad Linga
authors.initials: MV
authors.lastname: Reddy
authors.forename: Iulia
authors.initials: I
authors.lastname: Iatan
authors.forename: Daphna
authors.initials: D
authors.lastname: Weissglas-Volkov
authors.forename: Elina
authors.initials: E
authors.lastname: Nikkola
authors.forename: Blake E
authors.initials: BE
authors.lastname: Haas
authors.forename: Miina
authors.initials: M
authors.lastname: Juvonen
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ruel
authors.forename: Miina Juvonen Isabelle
authors.initials: MJ
authors.lastname: Ruel
authors.forename: Janet S
authors.initials: JS
authors.lastname: Sinsheimer
authors.forename: Jacques
authors.initials: J
authors.lastname: Genest
authors.forename: Päivi
authors.initials: P
authors.lastname: Pajukanta
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000483:Alleles; D002478:Cells, Cultured; D008078:Cholesterol, LDL / Q000235:genetics* / Q000378:metabolism; D059472:Exome / Q000235:genetics*; D005190:Family; D008040:Genetic Linkage; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D008071:Lipoprotein Lipase / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D017422:Sequence Analysis, DNA; D012737:Sex Factors
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D008078:Cholesterol, LDL; D008071:Lipoprotein Lipase