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

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

doi:10.1016/j.cmet.2021.01.001

Abstract

SummarySkeletal 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.

Highlights

Patients with type 2 diabetes (T2D) have increased bone mineral density (BMD) yet greater susceptibility to fracture (Vestergaard, 2007)
We discovered that the Genome-wide association studies (GWASs) signal was driven by rs56371916, an intronic variant in adenylate cyclase 5 (ADCY5) that alters the binding affinity of sterol regulatory-element-binding protein 1 (SREBP1) and leads to differential ADCY5 gene expression and cell-autonomous changes in fatty acid metabolism in mature adipocytes and differentiating osteoblasts
We focused on adipocytes, osteoblasts, and mesenchymal stem cells (MSCs),; these cell types had among the highest levels of enrichment for Polycomb-repressed chromatin (Figure 2A)

Summary

Introduction

Patients with type 2 diabetes (T2D) have increased bone mineral density (BMD) yet greater susceptibility to fracture (Vestergaard, 2007) This perplexing finding suggests an intimate link between skeletal and metabolic traits. Genome-wide association studies (GWASs) have identified tens of thousands of genomic loci underlying individual human traits, including BMD and glycemic traits, of which the latter consists of fasting glucose, fasting insulin, HOMA-IR, and HOMA-B. These GWAS-identified loci have only rarely been resolved into causal variants or resulted in enumerated underlying mechanisms due to several challenges (Eichler et al, 2010). A systematic study of pleiotropic loci represents an opportunity to discover biological mechanisms underlying the individual traits and further mechanisms that link these traits

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