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

Curtis R. Warren, John F. O'Sullivan, Max Friesen, Caroline E. Becker, Xiaoling Zhang, Poching Liu, Yoshiyuki Wakabayashi, Jordan E. Morningstar, Xu Shi, Jihoon Choi, Fang Xia, Derek T. Peters, Mary H.C. Florido, Alexander M. Tsankov, Eilene Duberow, Lauren Comisar, Jennifer Shay, Xin Jiang, Alexander Meissner, Kiran MusunuruSekar Kathiresan, Laurence Daheron, Jun Zhu, Robert E. Gerszten, Rahul C. Deo, Ramachandran S. Vasan, Christopher J. O'Donnell, Chad A. Cowan

Research output: Contribution to journalArticlepeer-review

87 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)547-557.e7
JournalCell Stem Cell
Volume20
Issue number4
DOIs
StatePublished - Apr 6 2017
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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