Publication date: 6 April 2017
Source:Cell Stem Cell, Volume 20, Issue 4
Author(s): 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 Musunuru, Sekar Kathiresan, Laurence Daheron, Jun Zhu, Robert E. Gerszten, Rahul C. Deo, Ramachandran S. Vasan, Christopher J. O'Donnell, Chad A. Cowan
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.
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Teaser
As part of the NHLBI NextGen consortium, Warren et al. show that analyzing the cellular pathophysiology of cells differentiated from multiple lines of an iPSC library is a promising complementary approach in the functional analysis of GWAS variants.http://ift.tt/2p8DfL7
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