Key result
Specific genetic loci and advanced maternal age significantly increase ventricular septal defect risk in mice.
Why the study?
The multifactorial basis of congenital heart defects, specifically ventricular septal defects caused by Nkx2-5 mutation, lacks direct evidence and detailed understanding.
Effect estimate: LOD 5-7
p-value: p=1.7 x 10^-4
Hypothesis-generating in Nkx2-5 mice; leaves open human validation and clinical risk stratification.
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.
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Winston et al. (2012) studied Ventricular Septal Defects (n=3,100). Nkx2-5 mutation, genetic modifiers, and maternal age vs. Wild-type animals / younger maternal age was evaluated on Susceptibility to membranous ventricular septal defects (LOD 5-7, p=1.7 x 10^-4). Genetic loci on chromosomes 6, 8, and 10 (LOD scores 5-7) and advanced maternal age (P=1.7x10^-4) significantly modify and increase the risk of ventricular septal defects in Nkx2-5(+/-) mice.