Evaluating the Contribution of Cell-Type Specific Alternative Splicing to Variation in Lipid Levels

Lipid levels are heritable traits associated with cardiovascular disease risk, and previous genome-wide association studies (GWAS) have identified 150+ loci associated with these traits – however, the genetic mechanisms underlying most of these loci are not well understood. Recent research indicates that changes in the abundance of alternatively spliced transcripts may be an important mechanism contributing to complex traits. With the increased viability of induced pluripotent stem cells (iPSCs) and iPSC-derived hepatocyte-like cells (HLCs), understanding whether these models can be used to interrogate lipid biology is of increasing interest. Consequently, identifying genetic loci that associate with alternative splicing (i.e., sQTLs) in these cells and determining the degree to which these loci are informative for lipid biology would be ideal, but has not been described to date. We present sQTL discovery efforts using data from samplematched iPSC and HLC lines, as well as from a separate set of primary liver samples. Genes that are differentially spliced between iPSC and HLC cells are enriched for insulin signaling and lipid metabolism pathways. HLC sQTLs co-localize with GWAS lipid loci unexplained using HLC eQTL data alone, and at least 20% of sQTLs discovered in one stem cell type are not identified in the other cell type. Further, replication analysis indicates that HLC sQTLs more closely represent primary liver sQTLs compared to iPSC sQTLs. Our results provide an important foundation for efforts that use iPSC and iPSC-derived cells to evaluate genetic mechanisms influencing cardiovascular disease risk and complex traits in general.