A regulatory variant at 3q21.1 confers an increased pleiotropic risk for hyperglycemia and altered bone mineral density

Nasa Sinnott-Armstrong; Isabel S. Sousa; Samantha Laber; Elizabeth Rendina-Ruedy; Simon E. Nitter Dankel; Teresa Ferreira; Gunnar Mellgren; David Karasik; Manuel Rivas; Jonathan Pritchard; Anyonya R. Guntur; Roger D. Cox; Cecilia M. Lindgren; Hans Hauner; Richard Sallari; Clifford J. Rosen; Yi Hsiang Hsu; Eric S. Lander; Douglas P. Kiel; Melina Claussnitzer

doi:10.1016/j.cmet.2021.01.001

A regulatory variant at 3q21.1 confers an increased pleiotropic risk for hyperglycemia and altered bone mineral density

Nasa Sinnott-Armstrong, Isabel S. Sousa, Samantha Laber, Elizabeth Rendina-Ruedy, Simon E. Nitter Dankel, Teresa Ferreira, Gunnar Mellgren, David Karasik, Manuel Rivas, Jonathan Pritchard, Anyonya R. Guntur, Roger D. Cox, Cecilia M. Lindgren, Hans Hauner, Richard Sallari, Clifford J. Rosen, Yi Hsiang Hsu, Eric S. Lander, Douglas P. Kiel, Melina Claussnitzer

Bar-Ilan University - Azrieli Faculty of Medicine

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

Abstract

Nasa Sinnott-Armstrong and colleagues identify a pleiotropic risk locus at 3q21 that is associated with type 2 diabetes (T2D) and greater bone mineral density (BMD) and its associated cell-autonomous mechanisms in adipocytes and osteoblasts. Together, these findings provide a possible explanation for the perplexing finding that individuals with T2D have higher BMD but greater susceptibility to bone fracture.

Original language	English
Pages (from-to)	615-628.e13
Journal	Cell Metabolism
Volume	33
Issue number	3
DOIs	https://doi.org/10.1016/j.cmet.2021.01.001
State	Published - 2 Mar 2021

Bibliographical note

Publisher Copyright:
© 2021

Funding

We thank the Oxford Genomics Centre at the Wellcome Centre for Human Genetics (funded by Wellcome Trust grant reference 203141/Z/16/Z ) for the generation and initial processing of the sequencing data. N.S.-A. was funded by the Department of Defense through a National Defense Science and Engineering Grant and by a Stanford Graduate Fellowship . S.L. was funded by a Postdoctoral Research Fellowship funded by Novo Nordisk . The work was supported by M.C.’s Next Generation award of the Broad Institute of MIT and Harvard . The work was supported by the Else Kröner-Fresenius-Foundation and Clinical Cooperation Group “ Nutrigenomics and Type 2 Diabetes ,” German Center of Diabetes Research , Helmholtz Center Munich . D.P.K. was supported by a grant from the National Institute of Arthritis, Musculoskeletal and Skin Diseases ( R01 AR041398 ). We thank H. Ollila for helpful comments. We thank the Oxford Genomics Centre at the Wellcome Centre for Human Genetics (funded by Wellcome Trust grant reference 203141/Z/16/Z) for the generation and initial processing of the sequencing data. N.S.-A. was funded by the Department of Defense through a National Defense Science and Engineering Grant and by a Stanford Graduate Fellowship. S.L. was funded by a Postdoctoral Research Fellowship funded by Novo Nordisk. The work was supported by M.C.’s Next Generation award of the Broad Institute of MIT and Harvard. The work was supported by the Else Kröner-Fresenius-Foundation and Clinical Cooperation Group “Nutrigenomics and Type 2 Diabetes,” German Center of Diabetes Research, Helmholtz Center Munich. D.P.K. was supported by a grant from the National Institute of Arthritis, Musculoskeletal and Skin Diseases (R01 AR041398). We thank H. Ollila for helpful comments. Conceptualization, M.C. D.P.K. C.R. and E.S.L.; methodology, N.S.-A. S.L. and M.C.; investigation, N.S.-A. I.S. S.L. E.R.-R. S.E.N.D. and A.R.G.; analysis, N.S.-A. X.C. Y.-H.H. M.C. R.S. and D.K.; resources, M.R. G.M. H.H. M.C. and D.P.K.; writing – original draft, M.C. N.S.-A. R.S. I.S. S.L. E.-S.L. D.P.K. C.R.; writing – review & editing, all co-authors; supervision, M.C. D.P.K. C.R. H.H. and J.K.P. E.S.L. serves on the Board of Directors for Codiak BioSciences and serves on the Scientific Advisory Board of F-Prime Capital Partners and Third Rock Ventures; he is also affiliated with several non-profit organizations including serving on the Board of Directors of the Innocence Project, Count Me In, and Biden Cancer Initiative and the Board of Trustees for the Parker Institute for Cancer Immunotherapy. He has served and continues to serve on various federal advisory committees. C.M.L. received research support from Bayer Ag and Novo Nordisk and received honoraria or consultancy fees from Pfizer. D.P.K. serves as a member of a scientific advisory committee for Solarea Bio, has received grants to his institution from Radius Health and Amgen, and receives royalties for publication in UpToDate.

Funders	Funder number
Biden Cancer Initiative
Board of Trustees
F-Prime Capital Partners and Third Rock Ventures
Helmholtz Center Munich
Radius Health and Amgen
U.S. Department of Defense
National Institute of Arthritis and Musculoskeletal and Skin Diseases	R01AR041398
Stanford University
Harvard University
Wellcome Trust	203141/Z/16/Z
Broad Institute
Novo Nordisk

Keywords

CRISPR-Cas9 variant editing
osteoblast and adipocyte metabolism
pleiotropy of type 2 diabetes and bone mineral density
regulatory genomics
variant-to-function study

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.cmet.2021.01.001

Cite this

Sinnott-Armstrong, N., Sousa, I. S., Laber, S., Rendina-Ruedy, E., Nitter Dankel, S. E., Ferreira, T., Mellgren, G., Karasik, D., Rivas, M., Pritchard, J., Guntur, A. R., Cox, R. D., Lindgren, C. M., Hauner, H., Sallari, R., Rosen, C. J., Hsu, Y. H., Lander, E. S., Kiel, D. P., & Claussnitzer, M. (2021). A regulatory variant at 3q21.1 confers an increased pleiotropic risk for hyperglycemia and altered bone mineral density. Cell Metabolism, 33(3), 615-628.e13. https://doi.org/10.1016/j.cmet.2021.01.001

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abstract = "Nasa Sinnott-Armstrong and colleagues identify a pleiotropic risk locus at 3q21 that is associated with type 2 diabetes (T2D) and greater bone mineral density (BMD) and its associated cell-autonomous mechanisms in adipocytes and osteoblasts. Together, these findings provide a possible explanation for the perplexing finding that individuals with T2D have higher BMD but greater susceptibility to bone fracture.",

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Sinnott-Armstrong, N, Sousa, IS, Laber, S, Rendina-Ruedy, E, Nitter Dankel, SE, Ferreira, T, Mellgren, G, Karasik, D, Rivas, M, Pritchard, J, Guntur, AR, Cox, RD, Lindgren, CM, Hauner, H, Sallari, R, Rosen, CJ, Hsu, YH, Lander, ES, Kiel, DP & Claussnitzer, M 2021, 'A regulatory variant at 3q21.1 confers an increased pleiotropic risk for hyperglycemia and altered bone mineral density', Cell Metabolism, vol. 33, no. 3, pp. 615-628.e13. https://doi.org/10.1016/j.cmet.2021.01.001

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AU - Sousa, Isabel S.

AU - Laber, Samantha

AU - Rendina-Ruedy, Elizabeth

AU - Nitter Dankel, Simon E.

AU - Ferreira, Teresa

AU - Mellgren, Gunnar

AU - Karasik, David

AU - Rivas, Manuel

AU - Pritchard, Jonathan

AU - Guntur, Anyonya R.

AU - Cox, Roger D.

AU - Lindgren, Cecilia M.

AU - Hauner, Hans

AU - Sallari, Richard

AU - Rosen, Clifford J.

AU - Hsu, Yi Hsiang

AU - Lander, Eric S.

AU - Kiel, Douglas P.

AU - Claussnitzer, Melina

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KW - variant-to-function study

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A regulatory variant at 3q21.1 confers an increased pleiotropic risk for hyperglycemia and altered bone mineral density

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

Access to Document

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Cite this