Precision Medicine Technologies
Systematic Data-Based Approaches for Precision Medicine
It has been hypothesized that many disease-causing variants exert their effects during development, rather than in adult cells. However, it is difficult to identify these variants and their effects as they could act in multiple different cell types, and there was a recent moratorium on research using fetal tissue. We recently established that iPSC-derived cardiovascular progenitor cells (CVPCs) are fetal-like, and can be utilized to identify cardiac regulatory variants. Here, we leveraged this system to identify fetal cell-type specific eQTLs that underlie GWAS signals for adult cardiac diseases. We started by characterizing the differentiation of iPSCs into iPSC-CVPCs via scRNA-seq on eight samples, and found they were comprised of two cardiac cell types: cardiomyocytes (CMs) and epicardium derived cells (EPDCs). Next, we derived 180 iPSC-CVPCs, performed bulk RNA-seq, and used the scRNA-seq expression signatures to deconvolute and determine the relative proportions of CMs and EPDCs in each sample. We integrated these data with WGS and identified cell type-specific eQTLs (associated with only CMs or EPDCs). We next identified fetal-specific eQTLs by colocalizing our iPSC-CVPC eQTLs with all GTEx adult cardiac tissue eQTLs. To identify variants underlying the fetal origin of complex adult cardiac traits, we colocalized these fetal-specific eQTLs with cardiac traits GWAS summary statistics (pulse rate and myocardial infarction), and found 10 fetal-specific eGenes, including CLPTM1 which has previously been associated with congenital malformations (as expected for a fetal-acting gene). Our findings provide genetic evidence supporting the fetal origin of cardiovascular disease and show that iPSC-derived tissues can be leveraged to study the fetal origins of diseases in relevant cell-types.