Shared Genetic Architecture between Muscle and Bone: Identification and Functional Implications of EPDR1, PKDCC, and SPTBN1

Abstract

Recent studies suggest a shared genetic architecture between muscle and bone, yet the underlying molecular mechanisms remain elusive. This study aims to identify the functionally annotated genes with shared genetic architecture between muscle and bone using the most up-to-date genome-wide association study (GWAS) summary statistics from bone mineral density (BMD) and fracture-related genetic variants. We employed an advanced statistical functional mapping method to investigate shared genetic architecture between muscle and bone, focusing on genes highly expressed in muscle tissue. Our analysis identified three genes, EPDR1, PKDCC, and SPTBN1, highly expressed in muscle tissue and previously unlinked to bone metabolism. About 90% and 85% of filtered Single-Nucleotide Polymorphisms were located in the intronic and intergenic regions for the threshold at P [≤] 5 x 10-8 and P [≤] 5 x 10-100, respectively. EPDR1 was highly expressed in multiple tissues, including muscle, adrenal gland, blood vessels, and thyroid. SPTBN1 was highly expressed in all 30 tissue types except blood, while PKDCC was highly expressed in all 30 tissue types except the brain, pancreas, and skin. Our study provides a framework for using GWAS findings to highlight functional evidence of crosstalk between multiple tissues based on shared genetic architecture between muscle and bone. Further research should focus on functional validation, multi-omics data integration, gene-environment interactions, and clinical relevance in musculoskeletal disorders. Author SummaryOsteoporotic fractures in the aging population pose a significant health concern. They are often attributed to decreased bone strength and muscle loss. However, the underlying molecular connections between bone and muscle are not well understood. This lack of knowledge persists despite recent genetic discoveries linking certain genetic variants to bone mineral density and fracture risk. Our study aimed to uncover genes that share genetic architecture between muscle and bone. We utilized state-of-the-art statistical methods and the most recent genetic data related to bone mineral density and fractures. Our focus was on genes that are highly active in muscle tissue. Our investigation identified three new genes - EPDR1, PKDCC, and SPTBN1 - which are highly active in muscle tissue and influence bone health. These discoveries offer fresh insights into the interconnected genetic makeup of bone and muscle. Our work not only uncovers potential targets for therapeutic strategies to enhance bone and muscle strength but also provides a blueprint for identifying shared genetic structures across multiple tissues. This research represents a crucial step forward in our understanding of the interplay between our muscles and bones at a genetic level.