Large diverse population cohorts of hiPSCs and derived hepatocyte-like cells reveal functional genetic variation at blood lipid-associated loci
| Autor: | 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 |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Induced Pluripotent Stem Cells Quantitative Trait Loci Genomics Genome-wide association study Biology Polymorphism Single Nucleotide Article Cohort Studies 03 medical and health sciences Mice Genetics Animals Humans Genetic Predisposition to Disease Induced pluripotent stem cell Gene Genetic association Base Sequence Gene Expression Profiling Genetic Variation Cell Biology Lipid Metabolism Phenotype Lipids 030104 developmental biology Liver Genetic Loci Organ Specificity Expression quantitative trait loci Hepatocytes Molecular Medicine Stem cell Genome-Wide Association Study |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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