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Large diverse population cohorts of hiPSCs and derived hepatocyte-like cells reveal functional genetic variation at blood lipid-associated loci
- 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.
- Subjects :
- 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
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....04910c1927c398d2db28452860f800f0