PuSH - Publication Server of Helmholtz Zentrum München: A regulatory variant at <em>3q21.1</em> confers an increased pleiotropic risk for hyperglycemia and altered bone mineral density.

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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.*

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

Cell Metab. 33, 615-628.e13 (2021)

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Skeletal and glycemic traits have shared etiology, but the underlying genetic factors remain largely unknown. To identify genetic loci that may have pleiotropic effects, we studied Genome-wide association studies (GWASs) for bone mineral density and glycemic traits and identified a bivariate risk locus at 3q21. Using sequence and epigenetic modeling, we prioritized an adenylate cyclase 5 (ADCY5) intronic causal variant, rs56371916. This SNP changes the binding affinity of SREBP1 and leads to differential ADCY5 gene expression, altering the chromatin landscape from poised to repressed. These alterations result in bone- and type 2 diabetes-relevant cell-autonomous changes in lipid metabolism in osteoblasts and adipocytes. We validated our findings by directly manipulating the regulator SREBP1, the target gene ADCY5, and the variant rs56371916, which together imply a novel link between fatty acid oxidation and osteoblast differentiation. Our work, by systematic functional dissection of pleiotropic GWAS loci, represents a framework to uncover biological mechanisms affecting pleiotropic traits.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Crispr-cas9 Variant Editing ; Osteoblast And Adipocyte Metabolism ; Pleiotropy Of Type 2 Diabetes And Bone Mineral Density ; Regulatory Genomics ; Variant-to-function Study; Genome-wide Association; Gene-expression; Heritability; Architecture; Obesity; Differentiation; Identification; Metaanalysis; Statistics; Inference

ISSN (print) / ISBN 1550-4131

e-ISSN 1932-7420

Journal Cell Metabolism

Quellenangaben Volume: 33, Issue: 3, Pages: 615-628.e13

Publisher Elsevier

Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) CCG Nutrigenomics and Type 2 Diabetes (KKG-KDN)

Grants National Institute of Arthritis, Musculoskeletal and Skin Diseases
Clinical Cooperation Group "Nutrigenomics and Type 2 Diabetes,'' German Center of Diabetes Research, Helmholtz Center Munich
Else Kroner-Fresenius-Foundation
Broad Institute of MIT and Harvard
Novo Nordisk
Stanford Graduate Fellowship
Department of Defense through a National Defense Science and Engineering Grant
Wellcome Trust