skip to Main Content

Award Pending

Genetic and Functional Genomic Analysis of Congenital Heart Defects

Research Summary:  Congenital heart disease (CHD) is the leading cause of premature death or lifelong disability, afflicting ~1% of live birth on average. Genetic and environmental contributions are potential underlying causes of CHD, and racial and ethnic differences are factors associated with heart defect rates. However, the detailed cellular molecular mechanisms remain poorly understood. Different types of CHDs show various rates across races/ethnicities. The total CHD rate in Hawaii State was 1.77% of births, significantly higher than the average national rate. Furthermore, some severe CHD types are significantly higher in minority races and ethnicities. Dissecting the genetic causality of CHD will help develop precision-guided strategies to prevent and treat CHDs. In addition, comorbidity, such as diabetes, is related to increased CHD incidents in offspring. The prevalence of diabetes and prediabetes is significantly higher in Hawaii. The University of Hawaii has established a large Human Reproductive Biospecimen Repository (Hawaii HiBR) comprising rich clinical data and biospecimens. Nonetheless, the relationship between diabetes and CHDs in this diverse cohort remains poorly understood, and so does the underlying biological basis of CHD. Overall Goals: Aligned with the overarching goals of the parent project, “Hawaii INBRE Program,” to strengthen biomedical research expertise and collaboration, this Supplements project contains two sub-projects, aiming to unravel genetic and functional genomic mechanisms of CHDs. In Sub-Project 1 (Aim 1), we will incorporate data science and machine learning models to perform integrative genome- and transcriptome-wide association (GTWA) analysis on the voluminous NIH TOPMed PCGC CHD data and the precious Hawaii HiBR resources. We will explore the interplays between genetic and epigenetic perturbations in CHD and associated comorbidities. In Sub-Project 2 (Aim 2), we will perform WXS and targeted genotyping of CHD hub genes and related epigenetic histone modifier genes in the Hawaii HiBR cohort. Non-synonymous mutations in epigenetic modifier genes are significantly associated with CHD, but functional significance remains largely undetermined. Here, we will examine the functional effects of the mutants of CHD hub genes and epigenetic modifier genes on the growth and cardiac functions of human-induced pluripotent stem cell-derived cardiomyocytes. This will be performed on a microelectrode array (MEA) system for high-throughput, multimodal assessments. Impacts and Significance: This study will enhance the scientific values of current large CHD datasets and precious biospecimen resources with unique race/ethnicity diversity. The study will generate in-depth insights into multiomics genotypes-phenotype association, allowing for improved CHD genetic classification and prediction of CHD outcomes. And the study will advance our knowledge of functional mechanisms of CHD genetic lesions and comorbidities. It will provide targets of genetics and epigenetics interventions to prevent and treat CHD and will help narrow the gaps in health disparities.


Back To Top