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Large diverse population cohorts of hiPSCs and derived hepatocyte-like cells reveal functional genetic variation at blood lipid-associated loci

Authors :
Christopher D. Brown
Sekar Kathiresan
Edward E. Morrisey
Evanthia E. Pashos
Kiran Musunuru
Juan Arbelaez
Zhaorui Lian
Tarjei S. Mikkelsen
Mayda Hernandez
Stacey L. Lytle-Gabbin
Dawn Marchadier
Nicolas Kuperwasser
YoSon Park
Xiao Wang
Wenjun Li
Ruilan Yan
Deepti Abbey
Xiaolan Zhang
Stephen A. Duncan
Ioannis M. Stylianou
Daniel J. Rader
Wenjian Lv
Jianting Shi
Derek T. Peters
Ying Liu
Peter Rogov
Wenli Yang
Katherine J. Slovik
Li Wang
Avanthi Raghavan
Publication Year :
2017

Abstract

Summary 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.

Details

Language :
English
Database :
OpenAIRE
Accession number :
edsair.doi.dedup.....04910c1927c398d2db28452860f800f0