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

Warren, C. R., O’Sullivan, J. F., Friesen, M., Becker, C. E., Zhang, X., Liu, P., et al. (2017). Induced Pluripotent Stem Cell Differentiation Enables Functional Validation of GWAS Variants in Metabolic Disease. Cell Stem Cell, 20(4), 547-557. doi:10.1016/j.stem.2017.01.010.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-DCED-9 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-DCEE-7
Genre: Journal Article

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 Creators:
Warren, Curtis R. , Author
O’Sullivan, John F. , Author
Friesen, Max, Author
Becker, Caroline E., Author
Zhang, Xiaoling , Author
Liu, Poching , Author
Wakabayashi, Yoshiyuki , Author
Morningstar, Jordan E. , Author
Shi, Xu, Author
Choi, Jihoon , Author
Xia, Fang, Author
Peters, Derek T. , Author
Florido, Mary H. C. , Author
Tsankov, Alexander M. , Author
Duberow, Eilene , Author
Comisar, Lauren , Author
Shay, Jennifer, Author
Jiang, Xin, Author
Meissner, Alexander1, 2, Author              
Musunuro, Kiran, Author
Kathiresan, Sekar , AuthorDaheron, Laurence , AuthorZhu, Jun, AuthorGerszten, Robert E. , AuthorDeo, Rahul C. , AuthorVasan, Ramachandran S. , AuthorO’Donnell, Christopher J. , AuthorCowan, Chad A. , Author more..
Affiliations:
1Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2379694              
2Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA, ou_persistent22              

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

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Language(s): eng - English
 Dates: 2017-04-06
 Publication Status: Published in print
 Pages: 11
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1016/j.stem.2017.01.010
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Title: Cell Stem Cell
Source Genre: Journal
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Publ. Info: Elsevier B.V.
Pages: - Volume / Issue: 20 (4) Sequence Number: - Start / End Page: 547 - 557 Identifier: -