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

Cell Metab. 2021 Mar 2;33(3):615-628.e13. doi: 10.1016/j.cmet.2021.01.001. Epub 2021 Jan 28.

Authors

Nasa Sinnott-Armstrong¹, Isabel S Sousa², Samantha Laber³, Elizabeth Rendina-Ruedy⁴, Simon E Nitter Dankel⁵, Teresa Ferreira⁶, Gunnar Mellgren⁵, David Karasik⁷, Manuel Rivas⁸, Jonathan Pritchard⁹, Anyonya R Guntur⁴, Roger D Cox¹⁰, Cecilia M Lindgren¹¹, Hans Hauner¹², Richard Sallari¹³, Clifford J Rosen⁴, Yi-Hsiang Hsu¹⁴, Eric S Lander¹⁵, Douglas P Kiel¹⁴, Melina Claussnitzer¹⁶

Affiliations

¹ 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 Genetics, Stanford University, Stanford 94305 CA, USA.
² 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.
³ 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, University of Oxford, Oxford, UK.
⁴ Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME 04074, USA.
⁵ 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.
⁶ Big Data Institute, University of Oxford, Oxford, UK.
⁷ 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.
⁸ Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA.
⁹ Department of Genetics, Stanford University, Stanford 94305 CA, USA; Department of Biology, Stanford University, Stanford, CA 94305, USA.
¹⁰ Medical Research Council Harwell, Oxfordshire, UK.
¹¹ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Big Data Institute, University of Oxford, Oxford, UK.
¹² 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 2 Diabetes" of the German Center of Diabetes Research, Helmholtz Center Munich, Munich 85764, Germany.
¹³ Metabolism Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹⁴ 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.
¹⁵ 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 Biology, MIT, Cambridge, MA 02142, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
¹⁶ 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 Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02131, USA; University of Hohenheim, Institute of Nutritional Science, Stuttgart 70599, Germany. Electronic address: melina@broadinstitute.org.

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.

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

Published by Elsevier Inc.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenylyl Cyclases / genetics
Adenylyl Cyclases / metabolism
Adipocytes / cytology
Adipocytes / metabolism
Adult
Bone Density / physiology*
Cell Differentiation
Cells, Cultured
Diabetes Mellitus, Type 2 / genetics
Diabetes Mellitus, Type 2 / pathology*
Female
Genetic Loci
Genome-Wide Association Study
Haplotypes
Humans
Lipid Peroxidation
Male
Middle Aged
Osteoblasts / cytology
Osteoblasts / metabolism
Polymorphism, Single Nucleotide*
Risk Factors
Stem Cells / cytology
Stem Cells / metabolism
Sterol Regulatory Element Binding Protein 1 / genetics
Sterol Regulatory Element Binding Protein 1 / metabolism

Substances

SREBF1 protein, human
Sterol Regulatory Element Binding Protein 1
Adenylyl Cyclases
adenylyl cyclase type V

Abstract

Publication types

MeSH terms

Substances

Grants and funding