Date of Award
Doctor of Philosophy (PhD)
Congenital heart disease (CHD) is the most common congenital anomaly, which makes it a leading cause of infant mortality. Congenital heart defects are a cluster of distinct developmental malformations that affect the vasculature, musculature and organization of the heart, each with varying clinical severity. Although medical and surgical advances have reduced CHD mortality in newborns and children, these patients grow up and many experience serious morbidity and early mortality. The first step toward reducing this burden is to understand the causes of CHD. Surprisingly, environmental insults and de novo mutations are estimated to explain less than one-third of CHD cases. In many cases, even when a vital cardiac gene is mutated, a heart defect does not occur. This highlights the critical role of genetic and environmental modifiers in CHD pathogenesis. Attempts to identify these modifiers have had marginal success in humans. This motivated us to model CHD in mice, in which we can control the effects of environment and genetics. Using nearly 20,000 Nkx2-5 heterozygous mutant mice from multiple inbred strain crosses, my work provides three key findings that describe how genetic and environmental risk factors modulate CHD risk. First, severe heart defects are rare because they require interactions between multiple risk alleles to manifest disease. Contrarily, mild heart defects can be caused by the Nkx2-5 mutation alone, which allows these defects to be common. Second, genetic robustness to deleterious mutations can result from well-integrated or coadapted genetic networks. In our mouse model, we found that epistatic interaction effects tend to suppress heart defect risk when the interacting alleles originate from the ancestral mouse strain. This suggests that the incomplete penetrance of human CHD-associated mutations is a result of varying levels of robustness to disease across individuals. Third, there is significant genetic variation in the maternal age associated risk of CHD, suggesting that the underlying genes can be identified. We recapitulated the human maternal age risk using a 56th generation advanced intercross mouse mother population and identified one genome-wide significant locus that modulates the age effect across different heart defect types. Modulating the associated molecular pathway may become a fruitful therapeutic target to suppress CHD risk. In conclusion, my work has uncovered multiple factors that contribute to congenital heart disease risk in humans. The importance of epistasis in CHD risk emphasizes the need to consider oligogenic disease models in whole-exome/genome and clinical genetics studies of CHD. Furthermore, maternal effects such as the maternal age effect may help identify modifiable molecular pathways that can suppress CHD risk in human populations. Future studies on the maternal age effect will focus on finalizing our statistical models and validating candidate genes in animal models.
Chair and Committee
Patrick Y. Jay
Shin-Ichiro Imai, Heather Lawson, Michael Province, Stacey Rentschler,
Akhirome, Ehiole Ogboma, "Genetic Interactions and Maternal Genes Modulate Congenital Heart Disease Risk" (2020). Arts & Sciences Electronic Theses and Dissertations. 2159.