Large, Diverse Population Cohorts of hiPSCs and Derived Hepatocyte-like Cells Reveal Functional Genetic Variation at Blood Lipid-Associated Loci

Evanthia E Pashos, YoSon Park, Xiao Wang, Avanthi Raghavan, Wenli Yang, Deepti Abbey, Derek T Peters, Juan Arbelaez, Mayda Hernandez, Nicolas Kuperwasser, Wenjun Li, Zhaorui Lian, Ying Liu, Wenjian Lv, Stacey L Lytle-Gabbin, Dawn H Marchadier, Peter Rogov, Jianting Shi, Katherine J Slovik, Ioannis M Stylianou, Li Wang, Ruilan Yan, Xiaolan Zhang, Sekar Kathiresan, Stephen A Duncan, Tarjei S Mikkelsen, Edward E Morrisey, Daniel J Rader, Christopher D Brown, Kiran Musunuru.
Cell Stem Cell. 2017-04-06;20(4):558-570.e10.
Genome-wide association studies have struggled to identify functional genes and variants underlying complex phenotypes. We recruited a multi-ethnic cohort of healthy volunteers (n = 91) and used their tissue to generate induced pluripotent stem cells (iPSCs) and hepatocyte-like cells (HLCs) for genome-wide mapping of expression quantitative trait loci (eQTLs) and allele-specific expression (ASE). We identified many eQTL genes (eGenes) not observed in the comparably sized Genotype-Tissue Expression project's human liver cohort (n = 96). Focusing on blood lipid-associated loci, we performed massively parallel reporter assays to screen candidate functional variants and used genome-edited stem cells, CRISPR interference, and mouse modeling to establish rs2277862-CPNE1, rs10889356-DOCK7, rs10889356-ANGPTL3, and rs10872142-FRK as functional SNP-gene sets. We demonstrated HLC eGenes CPNE1, VKORC1, UBE2L3, and ANGPTL3 and HLC ASE gene ACAA2 to be lipid-functional genes in mouse models. These findings endorse an iPSC-based experimental framework to discover functional variants and genes contributing to complex human traits.