title: Complex trait analysis of ventricular septal defects caused by Nkx2-5 mutation.
abstract: BACKGROUND
  The occurrence of a congenital heart defect has long been thought to have a multifactorial basis, but the evidence is indirect. Complex trait analysis could provide a more nuanced understanding of congenital heart disease.
  
  
  RESULTS
  We assessed the role of genetic and environmental factors on the incidence of ventricular septal defects (VSDs) caused by a heterozygous Nkx2-5 knockout mutation. We phenotyped >3100 hearts from a second-generation intercross of the inbred mouse strains C57BL/6 and FVB/N. Genetic linkage analysis mapped loci with lod scores of 5 to 7 on chromosomes 6, 8, and 10 that influence the susceptibility to membranous VSDs in Nkx2-5(+/-) animals. The chromosome 6 locus overlaps one for muscular VSD susceptibility. Multiple logistic regression analysis for environmental variables revealed that maternal age is correlated with the risk of membranous and muscular VSD in Nkx2-5(+/-) but not wild-type animals. The maternal age effect is unrelated to aneuploidy or a genetic polymorphism in the affected individuals. The risk of a VSD is not only complex but dynamic. Whereas the effect of genetic modifiers on risk remains constant, the effect of maternal aging increases over time.
  
  
  CONCLUSIONS
  Enumerable factors contribute to the presentation of a congenital heart defect. The factors that modify rather than cause congenital heart disease substantially affect risk in predisposed individuals. Their characterization in a mouse model offers the potential to narrow the search space in human studies and to develop alternative strategies for prevention.
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Julia B
authors.initials: JB
authors.lastname: Winston
authors.forename: Claire E
authors.initials: CE
authors.lastname: Schulkey
authors.forename: Iuan-Bor D
authors.initials: IB
authors.lastname: Chen
authors.forename: Suk D
authors.initials: SD
authors.lastname: Regmi
authors.forename: Maria
authors.initials: M
authors.lastname: Efimova
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Erlich
authors.forename: Courtney A
authors.initials: CA
authors.lastname: Green
authors.forename: Ashley
authors.initials: A
authors.lastname: Aluko
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Jay
mesh_terms: D000782:Aneuploidy; D000818:Animals; D056915:DNA Copy Number Variations; D005260:Female; D008040:Genetic Linkage; D006345:Heart Septal Defects, Ventricular / Q000235:genetics*; D006579:Heterozygote; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D016015:Logistic Models; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D011110:Polymorphism, Genetic; D012307:Risk Factors; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
chemical_list: D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C095552:NKX2-5 protein, human; D014157:Transcription Factors