"Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve"
Bicuspid aortic valve (BAV) is a congenital aortic valve defect characterized by fusion of two of the normal three leaflets. With a prevalence of ~1% in the population and a feature of some rare connective-tissue syndromes, BAV is the most common congenital heart defect in humans. The presence of a BAV confers an eight-fold increased risk of aortic dissection, which carries very high mortality. I will present a genome-wide association study (GWAS) we performed to identify genetic variants associated with BAV, leading to biological insights of the underlying causes. We identified association with a non-coding variant 151 kb from the cardiac-specific transcription factor, GATA4, and near-significance for p.Ser377Gly in GATA4. GATA4 was interrupted by CRISPR/Cas9 in induced pluripotent stem cells (iPSCs) from healthy donors. The disruption of GATA4 significantly impaired the transition from endothelial cells into mesenchymal cells, a critical step in heart valve development.
To uncover mechanisms of action of disease using genetic association, phenome-wide association studies (PheWAS) have become popular, in which GWAS are systematically performed for all diseases and traits that were collected from study participants in large biobanks. The second project I am going to present will be focused on developing statistical methods to address two main challenges in PheWAS analysis: 1. imbalanced case control sampling for most of the binary traits. 2. relatedness among research subjects.