1. A regulatory variant at 3q21.1 confers an increased pleiotropic risk for hyperglycemia and altered bone mineral density
- Author
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Manuel A. Rivas, Melina Claussnitzer, David Karasik, Douglas P. Kiel, Gunnar Mellgren, Jonathan K. Pritchard, Cecilia M. Lindgren, Teresa Ferreira, Nasa Sinnott-Armstrong, Anyonya R. Guntur, Richard C Sallari, Elizabeth Rendina-Ruedy, Roger D. Cox, Simon N. Dankel, Eric S. Lander, Isabel S. Sousa, Samantha Laber, Yi-Hsiang Hsu, Hans Hauner, and Clifford J. Rosen
- Subjects
Adult ,Male ,0301 basic medicine ,Physiology ,Crispr-cas9 Variant Editing ,Osteoblast And Adipocyte Metabolism ,Pleiotropy Of Type 2 Diabetes And Bone Mineral Density ,Regulatory Genomics ,Variant-to-function Study ,Locus (genetics) ,Genome-wide association study ,Biology ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,0302 clinical medicine ,pleiotropy of type 2 diabetes and bone mineral density ,regulatory genomics ,Bone Density ,Risk Factors ,Gene expression ,Adipocytes ,medicine ,Humans ,SNP ,Epigenetics ,Molecular Biology ,Cells, Cultured ,Genetic association ,Genetics ,variant-to-function study ,Osteoblasts ,Stem Cells ,CRISPR-Cas9 variant editing ,osteoblast and adipocyte metabolism ,Cell Differentiation ,Osteoblast ,Cell Biology ,Middle Aged ,Chromatin ,ddc ,030104 developmental biology ,medicine.anatomical_structure ,Diabetes Mellitus, Type 2 ,Haplotypes ,Genetic Loci ,Female ,Lipid Peroxidation ,Sterol Regulatory Element Binding Protein 1 ,030217 neurology & neurosurgery ,Adenylyl Cyclases ,Genome-Wide Association Study - Abstract
Summary 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., Graphical abstract, Highlights • 3q21 variants are associated with type 2 diabetes and increased bone mineral density • 3q21 variants affect chromatin accessibility in mesenchymal cells • rs56371916 is a 3q21 causal variant and ADCY5 its target in adipocytes and osteoblasts • ADCY5 and rs56371916 affect lipid oxidation processes in adipocytes and osteoblasts, 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.
- Published
- 2021