| First Author | Winston JB | Year | 2012 |
| Journal | Circ Cardiovasc Genet | Volume | 5 |
| Issue | 3 | Pages | 293-300 |
| PubMed ID | 22534315 | Mgi Jnum | J:317015 |
| Mgi Id | MGI:6843113 | Doi | 10.1161/CIRCGENETICS.111.961136 |
| Citation | Winston JB, et al. (2012) Complex trait analysis of ventricular septal defects caused by Nkx2-5 mutation. Circ Cardiovasc Genet 5(3):293-300 |
| abstractText | 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. METHODS AND 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. |
