In this study, we asked two overarching questions. First, can population cohorts of iPSCs and iPSC-differentiated cells be used to perform unbiased genome-wide eQTL/ASE studies in a manner that is complementary to traditional primary tissue-based studies such as the Gene-Tissue Expression (GTEx) project? Second, can we better understand the functional role of human genetic variation in influencing quantitative phenotypic traits, particularly those related to liver metabolism such as blood lipid levels? As part of the NHLBI Next Generation Genetic Association Studies Consortium, we generated population-based cohorts of iPSCs and iPSC-differentiated hepatocyte-like cells (HLCs) to perform genome-wide mapping and characterize known and new eQTL/ASE loci. We thereafter employed gene overexpression mouse models as well as a combination of MPRAs and CRISPR-Cas9 in hPSCs, other types of cultured cells, and mouse models to screen, identify, and validate functional variants and/or genes in several blood lipid-associated eQTL/ASE loci.
