期刊
CELL STEM CELL
卷 20, 期 4, 页码 558-+出版社
CELL PRESS
DOI: 10.1016/j.stem.2017.03.017
关键词
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资金
- Howard Hughes Medical Institute Medical Research Fellows Program
- NIH [R01-GM104464, R01-HL118744, R01-DK099571, U01-HG006398, RC2-HL101864, R01-MH101822]
- Harvard Stem Cell Institute
- NIH/NCATS [UL1-TR000003]
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 rs2277862CPNE1, 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.
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