Journal
CELL METABOLISM
Volume 3, Issue 3, Pages 615-+Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2021.01.001
Keywords
-
Categories
Funding
- Wellcome Trust [203141/Z/16/Z]
- Department of Defense through a National Defense Science and Engineering Grant
- Stanford Graduate Fellowship
- Novo Nordisk
- Broad Institute of MIT and Harvard
- Else Kroner-Fresenius-Foundation
- Clinical Cooperation Group Nutrigenomics and Type 2 Diabetes,'' German Center of Diabetes Research, Helmholtz Center Munich
- National Institute of Arthritis, Musculoskeletal and Skin Diseases [R01 AR041398]
- MRC [MC_U142661184] Funding Source: UKRI
Ask authors/readers for more resources
The study identified a bivariate risk locus at 3q21 and prioritized a causal variant in the adenylate cyclase 5 intron, which affects lipid metabolism in bone and diabetes-relevant cells. The findings were validated through manipulation of regulator SREBP1, target gene ADCY5, and variant rs56371916, suggesting a novel link between fatty acid oxidation and osteoblast differentiation. This work represents a framework for uncovering biological mechanisms affecting pleiotropic traits through systematic functional dissection of GWAS loci.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available