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Induced Pluripotent Stem Cell Differentiation Enables Functional Validation of GWAS Variants in Metabolic Disease.
Warren, Curtis R; O'Sullivan, John F; Friesen, Max; Becker, Caroline E; Zhang, Xiaoling; Liu, Poching; Wakabayashi, Yoshiyuki; Morningstar, Jordan E; Shi, Xu; Choi, Jihoon; Xia, Fang; Peters, Derek T; Florido, Mary H C; Tsankov, Alexander M; Duberow, Eilene; Comisar, Lauren; Shay, Jennifer; Jiang, Xin; Meissner, Alexander; Musunuru, Kiran; Kathiresan, Sekar; Daheron, Laurence; Zhu, Jun; Gerszten, Robert E; Deo, Rahul C; Vasan, Ramachandran S; O'Donnell, Christopher J; Cowan, Chad A.
Afiliación
  • Warren CR; Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
  • O'Sullivan JF; Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • Friesen M; Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
  • Becker CE; Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
  • Zhang X; School of Medicine, Boston University, Boston, MA 02118, USA; The Framingham Heart Study, Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Framingham, MA 01702, USA.
  • Liu P; DNA Sequencing and Genomics Core, National Heart Lung and Blood Institute, NIH, Bethesda, MD 20892, USA.
  • Wakabayashi Y; DNA Sequencing and Genomics Core, National Heart Lung and Blood Institute, NIH, Bethesda, MD 20892, USA.
  • Morningstar JE; Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • Shi X; Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • Choi J; Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
  • Xia F; Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
  • Peters DT; Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
  • Florido MHC; Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
  • Tsankov AM; Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Duberow E; Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
  • Comisar L; Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
  • Shay J; Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
  • Jiang X; Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
  • Meissner A; Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Musunuru K; Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
  • Kathiresan S; Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, 185 Cambridge Street, CPZN 5.252, Boston, MA 02114, USA.
  • Daheron L; Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
  • Zhu J; DNA Sequencing and Genomics Core, National Heart Lung and Blood Institute, NIH, Bethesda, MD 20892, USA.
  • Gerszten RE; Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • Deo RC; Cardiovascular Research Institute, Department of Medicine and Institute for Human Genetics, University of California, San Francisco, and California Institute for Quantitative Biosciences, San Francisco, CA 94143, USA.
  • Vasan RS; The Framingham Heart Study, Sections of Preventive Medicine and Epidemiology and Cardiology, Framingham, MA 01702, USA; School of Medicine, Boston University, Boston, MA 02118, USA; School of Public Health, Boston University, Boston, MA 02118, USA.
  • O'Donnell CJ; The Framingham Heart Study, Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Framingham, MA 01702, USA; Cardiology Section, Department of Medicine, Boston Veterans Administration Healthcare and Brigham and Women's Hospital, Boston, MA 02114, USA.
  • Cowan CA; Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: c
Cell Stem Cell ; 20(4): 547-557.e7, 2017 04 06.
Article en En | MEDLINE | ID: mdl-28388431
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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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Diferenciación Celular / Estudio de Asociación del Genoma Completo / Células Madre Pluripotentes Inducidas / Enfermedades Metabólicas Tipo de estudio: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Cell Stem Cell Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Diferenciación Celular / Estudio de Asociación del Genoma Completo / Células Madre Pluripotentes Inducidas / Enfermedades Metabólicas Tipo de estudio: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Cell Stem Cell Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos