With a birth prevalence of approximately 1/100, congenital heart defects (CHDs) are the most common birth defects and the leading cause of birth defect related infant mortality. CHDs cannot be cured and there are no population-based prevention strategies. Further, the specific causes of most CHDs are unknown. The gaps in our understanding of the causes of CHDs hamper our ability to prevent CHDs. Hence, the long-term goal of our research is to identify the causes of CHDs and to use this knowledge to develop CHD prevention strategies. To this end, we conducted a gene-level, genome-wide association study of conotruncal heart defects (CTDs) and the maternal genotype. The results of this study suggest the novel hypothesis that the maternal genotype influences embryonic heart development via maternal gene products present in the oocyte that direct early embryonic development. Maternal genes that affect embryonic development in this way are called maternal effect genes (MEGs). In our study, there was a 2-3 fold enrichment of mammalian MEGs among the maternal genes that were most significantly associated with CTDs (p<0.05). Our objective in this proposal is to identify the specific MEGs, and the variants within these MEGs, that are associated with CTDs. Specifically, our working hypothesis for the proposed studies is that maternal genotypes for a subset of MEGs are associated with the risk of CTDs and these associations extend to other types of CHDs, specifically left-sided cardiac lesions (LSLs). We will achieve our aims through secondary analyses of data from three large, independent, study cohorts: 1465 case-parent trios (670 CTD1; 478 CTD2; 317 LSLs) from the Children?s Hospital of Philadelphia; and 547 trios (355 CTDs, 192 LSLs) from the Pediatric Cardiac Genomics Consortium.
In Aim 1, we will identify the specific MEGs, and the variants within these MEGs, that are driving the observed MEG enrichment.
In Aim 2, we will evaluate MEGs in LSLs, to establish the specificity of MEG-CTD associations. In summary, our preliminary data provide support for a novel hypothesis about the role of the maternal genotype in the development of CHDs in offspring. Confirmation of this hypothesis would provide new insight into the causes of CHDs and, perhaps, other structural birth defects. Hence, the studies proposed in this application have the potential to significantly affect the fields of birth defect epidemiology and genetics, as well as public health efforts to prevent birth defects.

Public Health Relevance

In the United States, congenital heart defects are the most common birth defect (affecting about 1 in every 100 babies) and are the leading cause of birth defect related infant mortality. Congenital heart defects cannot be cured and there are no population-based approaches for prevention. The goal of our proposed studies is to identify maternal genes that are associated with the risk of heart defects in offspring and, ultimately, to translate this knowledge into approaches for preventing these life-threatening conditions.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HD097347-01A1
Application #
9821510
Study Section
Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
Program Officer
Toyama, Reiko
Project Start
2019-07-20
Project End
2021-06-30
Budget Start
2019-07-20
Budget End
2020-06-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Genetics
Type
Schools of Public Health
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77030