PROJECT SUMMARY
Cardiovascular disease (CVD) encompasses a broad range of diseases that are all characterized by damage or
dysfunction of cardiac tissue or blood vessels. According to the World Health Organization (WHO), CVD is the
leading cause of death in the United States. Despite its wide-spread prevalence, the factors that contribute to
the genetic predisposition for developing cardiovascular disease are still poorly understood. Genome-wide
association studies (GWAS) have identified ~1000 cardiac trait or disease-associated variants, but they fall short
of delineating causal genes and explaining the observed heritability and underlying molecular mechanisms. One
potential explanation for this shortcoming is that regulation of gene expression varies over a lifetime. It has been
hypothesized that a fraction of GWAS variants that contribute to the development of adult-onset cardiac disease
exert their effects during fetal development. Additionally, several studies have shown that developmental stage-
specific isoform switching occurs in cardiac genes that are involved in organogenesis, suggesting that regulatory
elements harboring genetic variants could control differential isoform usage between the fetal and adult stages.
However, due to the sparsity and controversial nature of studying fetal samples, a thorough investigation of these
hypotheses has not been conducted and the role of genetic variation in regulating gene expression in human
fetal cardiac tissues remains largely unstudied. Our lab has recently demonstrated that induced pluripotent stem
cell-derived cardiovascular progenitor cells (iPSC-CVPCs) are a powerful model system for studying genetic
variation across “fetal-like” cardiac samples derived from hundreds of individuals. Here, I propose to establish a
pipeline to elucidate and functionally characterize gene expression differences between fetal-like and adult
cardiac tissues, identify transcriptome-wide isoform switches between the two developmental stages, and
determine if regulatory variants associated with adult cardiac traits and disease phenotypes are active in fetal-
like tissues, adult tissues or at both stages of development. To accomplish these goals, I will leverage the gene
expression data from 180 iPSCORE iPSC-CVPCs generated in the Frazer laboratory and 430 samples from
adult cardiac left ventricle and atrial appendage tissues in the Genotype-Tissue Expression (GTEx) Program. In
Aim 1, I will evaluate differential gene expression and isoform usage to determine whether isoform switching is
a widespread phenomenon between fetal and adult stages. In Aim 2, I propose to create a developmental stage-
specific expression quantitative trait loci (eQTL) map for gene expression and isoform usage to identify regulatory
variants that are active in fetal-like and adult cardiac tissues. In Aim 3, I will use the fetal-like and adult cardiac
eQTLs, as well as epigenomic annotations, to fine map disease-causing variants for 87 cardiac trait and disease
GWAS studies. These findings could provide novel insights into fetal-specific and adult-specific
pathophysiological pathways that underlie complex cardiac disease phenotypes.