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

doi:10.1016/j.stem.2017.01.010

. 2017 Apr 6;20(4):547-557.e7.

doi: 10.1016/j.stem.2017.01.010.

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

Curtis R Warren¹, John F O'Sullivan², Max Friesen¹, Caroline E Becker¹, Xiaoling Zhang³, Poching Liu⁴, Yoshiyuki Wakabayashi⁴, Jordan E Morningstar², Xu Shi², Jihoon Choi¹, Fang Xia¹, Derek T Peters¹, Mary H C Florido¹, Alexander M Tsankov⁵, Eilene Duberow¹, Lauren Comisar¹, Jennifer Shay¹, Xin Jiang¹, Alexander Meissner⁵, Kiran Musunuru¹, Sekar Kathiresan⁶, Laurence Daheron¹, Jun Zhu⁴, Robert E Gerszten², Rahul C Deo⁷, Ramachandran S Vasan⁸, Christopher J O'Donnell⁹, Chad A Cowan¹⁰

Affiliations

¹ Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
² Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
³ 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.
⁴ DNA Sequencing and Genomics Core, National Heart Lung and Blood Institute, NIH, Bethesda, MD 20892, USA.
⁵ 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.
⁶ Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, 185 Cambridge Street, CPZN 5.252, Boston, MA 02114, USA.
⁷ 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.
⁸ 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.
⁹ 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.
¹⁰ 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: [email protected].

PMID: 28388431
DOI: 10.1016/j.stem.2017.01.010

Free article

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

Curtis R Warren et al. Cell Stem Cell. 2017.

Free article

. 2017 Apr 6;20(4):547-557.e7.

doi: 10.1016/j.stem.2017.01.010.

Authors

Affiliations

¹ Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
² Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
³ 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.
⁴ DNA Sequencing and Genomics Core, National Heart Lung and Blood Institute, NIH, Bethesda, MD 20892, USA.
⁵ 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.
⁶ Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, 185 Cambridge Street, CPZN 5.252, Boston, MA 02114, USA.
⁷ 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.
⁸ 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.
⁹ 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.
¹⁰ 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: [email protected].

PMID: 28388431
DOI: 10.1016/j.stem.2017.01.010

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.

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

PubMed Disclaimer

Cited by

Derivation of Thyroid Follicular Cells From Pluripotent Stem Cells: Insights From Development and Implications for Regenerative Medicine.
Posabella A, Alber AB, Undeutsch HJ, Droeser RA, Hollenberg AN, Ikonomou L, Kotton DN. Posabella A, et al. Front Endocrinol (Lausanne). 2021 Apr 20;12:666565. doi: 10.3389/fendo.2021.666565. eCollection 2021. Front Endocrinol (Lausanne). 2021. PMID: 33959101 Free PMC article. Review.
Intersection of Diet and Exercise with the Gut Microbiome and Circulating Metabolites in Male Bodybuilders: A Pilot Study.
Luk AWS, Mitchell L, Koay YC, O'Sullivan JF, O'Connor H, Hackett DA, Holmes A. Luk AWS, et al. Metabolites. 2022 Sep 27;12(10):911. doi: 10.3390/metabo12100911. Metabolites. 2022. PMID: 36295813 Free PMC article.
Human-specific genetics: new tools to explore the molecular and cellular basis of human evolution.
Pollen AA, Kilik U, Lowe CB, Camp JG. Pollen AA, et al. Nat Rev Genet. 2023 Oct;24(10):687-711. doi: 10.1038/s41576-022-00568-4. Epub 2023 Feb 3. Nat Rev Genet. 2023. PMID: 36737647 Free PMC article. Review.
FAM13A affects body fat distribution and adipocyte function.
Fathzadeh M, Li J, Rao A, Cook N, Chennamsetty I, Seldin M, Zhou X, Sangwung P, Gloudemans MJ, Keller M, Attie A, Yang J, Wabitsch M, Carcamo-Orive I, Tada Y, Lusis AJ, Shin MK, Molony CM, McLaughlin T, Reaven G, Montgomery SB, Reilly D, Quertermous T, Ingelsson E, Knowles JW. Fathzadeh M, et al. Nat Commun. 2020 Mar 19;11(1):1465. doi: 10.1038/s41467-020-15291-z. Nat Commun. 2020. PMID: 32193374 Free PMC article.
Human Stem Cell Models of SARS-CoV-2 Infection in the Cardiovascular System.
Ernzen K, Trask AJ, Peeples ME, Garg V, Zhao MT. Ernzen K, et al. Stem Cell Rev Rep. 2021 Dec;17(6):2107-2119. doi: 10.1007/s12015-021-10229-4. Epub 2021 Aug 8. Stem Cell Rev Rep. 2021. PMID: 34365591 Free PMC article. Review.

See all "Cited by" articles

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
- Elsevier Science
Other Literature Sources
- The Lens - Patent Citations Database
- scite Smart Citations
Medical
- MedlinePlus Health Information
Research Materials
- Addgene Non-profit plasmid repository
- Cellosaurus - a cell line knowledge resource
Miscellaneous
- SciCrunch

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Similar articles

Cited by

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Research Materials

Miscellaneous

Abstract

Similar articles

Cited by

Publication types

MeSH terms

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Research Materials

Miscellaneous