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A regulatory variant at 3q21.1 confers an increased pleiotropic risk for hyperglycemia and altered bone mineral density.
Sinnott-Armstrong, Nasa; Sousa, Isabel S; Laber, Samantha; Rendina-Ruedy, Elizabeth; Nitter Dankel, Simon E; Ferreira, Teresa; Mellgren, Gunnar; Karasik, David; Rivas, Manuel; Pritchard, Jonathan; Guntur, Anyonya R; Cox, Roger D; Lindgren, Cecilia M; Hauner, Hans; Sallari, Richard; Rosen, Clifford J; Hsu, Yi-Hsiang; Lander, Eric S; Kiel, Douglas P; Claussnitzer, Melina.
Afiliação
  • Sinnott-Armstrong N; Metabolism Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Cell Circuits and Epigenomics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Genet
  • Sousa IS; Metabolism Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Else Kröner-Fresenius-Center for Nutritional Medicine, School of Life Sciences, Technical University of Munich, Freising 85354, Germany.
  • Laber S; Metabolism Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Cell Circuits and Epigenomics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Big Data Institute,
  • Rendina-Ruedy E; Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME 04074, USA.
  • Nitter Dankel SE; University of Bergen, Bergen 5020, Norway; Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, 5020 Bergen, Norway; Hormone Laboratory, Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, 5021 Bergen, Norway.
  • Ferreira T; Big Data Institute, University of Oxford, Oxford, UK.
  • Mellgren G; University of Bergen, Bergen 5020, Norway; Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, 5020 Bergen, Norway; Hormone Laboratory, Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, 5021 Bergen, Norway.
  • Karasik D; Institute for Aging Research, Hebrew SeniorLife and Harvard Medical School, Boston, MA 02131, USA; Faculty of Medicine of the Galilee, Bar-Ilan University, Safed, Israel.
  • Rivas M; Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA.
  • Pritchard J; Department of Genetics, Stanford University, Stanford 94305 CA, USA; Department of Biology, Stanford University, Stanford, CA 94305, USA.
  • Guntur AR; Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME 04074, USA.
  • Cox RD; Medical Research Council Harwell, Oxfordshire, UK.
  • Lindgren CM; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Big Data Institute, University of Oxford, Oxford, UK.
  • Hauner H; Else Kröner-Fresenius-Center for Nutritional Medicine, School of Life Sciences, Technical University of Munich, Freising 85354, Germany; Institute of Nutritional Medicine, School of Medicine, Technical University of Munich, Freising 85354, Germany; Clinical Cooperation Group "Nutrigenomics and Type
  • Sallari R; Metabolism Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Rosen CJ; Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME 04074, USA.
  • Hsu YH; Institute for Aging Research, Hebrew SeniorLife and Harvard Medical School, Boston, MA 02131, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02131, USA.
  • Lander ES; Metabolism Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Cell Circuits and Epigenomics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Biolo
  • Kiel DP; Institute for Aging Research, Hebrew SeniorLife and Harvard Medical School, Boston, MA 02131, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02131, USA.
  • Claussnitzer M; Metabolism Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Cell Circuits and Epigenomics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medic
Cell Metab ; 33(3): 615-628.e13, 2021 03 02.
Article em En | MEDLINE | ID: mdl-33513366
ABSTRACT
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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Densidade Óssea / Polimorfismo de Nucleotídeo Único / Diabetes Mellitus Tipo 2 Tipo de estudo: Etiology_studies / Prognostic_studies / Risk_factors_studies Limite: Adult / Female / Humans / Male / Middle aged Idioma: En Revista: Cell Metab Assunto da revista: METABOLISMO Ano de publicação: 2021 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Densidade Óssea / Polimorfismo de Nucleotídeo Único / Diabetes Mellitus Tipo 2 Tipo de estudo: Etiology_studies / Prognostic_studies / Risk_factors_studies Limite: Adult / Female / Humans / Male / Middle aged Idioma: En Revista: Cell Metab Assunto da revista: METABOLISMO Ano de publicação: 2021 Tipo de documento: Article