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

Cell stem cell | Apr 6, 2017

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.

Pubmed ID: 28388432 RIS Download

Mesh terms: Animals | Base Sequence | Cohort Studies | Gene Expression Profiling | Genetic Loci | Genetic Predisposition to Disease | Genetic Variation | Genome-Wide Association Study | Hepatocytes | Humans | Induced Pluripotent Stem Cells | Lipid Metabolism | Lipids | Liver | Mice | Organ Specificity | Polymorphism, Single Nucleotide | Quantitative Trait Loci

Data used in this publication

None found

Associated grants

  • Agency: NIDDK NIH HHS, Id: P30 DK050306
  • Agency: Howard Hughes Medical Institute, Id: RC2 HL101864
  • Agency: NHLBI NIH HHS, Id: P30 CA138313
  • Agency: NCI NIH HHS, Id: R01 DK099571
  • Agency: NIDDK NIH HHS, Id: UL1 TR000003
  • Agency: NCATS NIH HHS, Id: R01 GM104464
  • Agency: NIGMS NIH HHS, Id: R01 MH101822
  • Agency: NIMH NIH HHS, Id: R01 DK102716
  • Agency: NIDDK NIH HHS, Id: R01 HL118744
  • Agency: NHLBI NIH HHS, Id: U01 HG006398
  • Agency: NHGRI NIH HHS, Id:

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