Induced Pluripotent Stem Cell Differentiation Enables Functional Validation of GWAS Variants in Metabolic Disease

Cell Stem Cell. 2017 Apr 6;20(4):547-557.e7. doi: 10.1016/j.stem.2017.01.010.


Genome-wide association studies (GWAS) have highlighted a large number of genetic variants with potential disease association, but functional analysis remains a challenge. Here we describe an approach to functionally validate identified variants through differentiation of induced pluripotent stem cells (iPSCs) to study cellular pathophysiology. We collected peripheral blood cells from Framingham Heart Study participants and reprogrammed them to iPSCs. We then differentiated 68 iPSC lines into hepatocytes and adipocytes to investigate the effect of the 1p13 rs12740374 variant on cardiometabolic disease phenotypes via transcriptomics and metabolomic signatures. We observed a clear association between rs12740374 and lipid accumulation and gene expression in differentiated hepatocytes, in particular, expression of SORT1, CELSR2, and PSRC1, consistent with previous analyses of this variant using other approaches. Initial investigation of additional SNPs also highlighted correlations with gene expression. These findings suggest that iPSC-based population studies hold promise as tools for the functional validation of GWAS variants.

Keywords: Framingham Heart Study; RNA sequencing; SORT1; adipocytes; cardiovascular disease; directed differentiation; expression quantitative trait locus; hepatocyte-like cells; induced pluripotent stem cells; metabolomics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes, White / cytology
  • Adipocytes, White / metabolism
  • Cell Differentiation / genetics*
  • Cellular Reprogramming / genetics
  • Chromosomes, Human, Pair 1 / genetics
  • Cohort Studies
  • Down-Regulation / genetics
  • Genome-Wide Association Study*
  • Genotype
  • Hepatocytes / cytology
  • Humans
  • Induced Pluripotent Stem Cells / cytology*
  • Induced Pluripotent Stem Cells / metabolism
  • Leukocytes, Mononuclear / metabolism
  • Lipid Metabolism / genetics
  • Metabolic Diseases / genetics*
  • Metabolomics
  • Models, Genetic
  • Phenotype
  • Quantitative Trait Loci / genetics
  • Reproducibility of Results
  • Sequence Analysis, RNA
  • Tissue Donors
  • Transcriptome / genetics