Genetic Links Between Metabolic Syndrome and Osteoarthritis: Insights from Cross-Trait Analysis

Abstract Context Previous observational studies have indicated a bidirectional association between metabolic syndrome (MetS) and osteoarthritis (OA). However, it remains unclear whether these bidirectional associations reflect causal relationships or shared genetic factors, and the underlying biological mechanisms of this association are not fully understood. Objective We aimed to explore the genetic connection between MetS and OA using genome-wide association study (GWAS) summary data. Methods Leveraging summary statistics from GWAS conducted by the UK Biobank and the Glucose and Insulin-related Traits Consortium (MAGIC), we performed global genetic correlation analyses, genome-wide cross-trait meta-analyses, and a bidirectional two-sample Mendelian randomization analyses using summary statistics from GWAS to comprehensively assess the relationship of MetS and OA. Results We first detected an extensive genetic correlation between MetS and OA (rg = 0.393, P = 1.52 × 10−18), which was consistent in 4 MetS components, including waist circumference, triglycerides, hypertension, and high-density lipoprotein cholesterol and OA with rg ranging from −0.229 to 0.490. We then discovered 32 variants jointly associated with MetS and OA through Multi-Trait Analysis of GWAS (MTAG). Co-localization analysis found 12 genes shared between MetS and OA, with functional implications in several biological pathways. Finally, Mendelian randomization analysis suggested genetic liability to MetS significantly increased the risk of OA, but no reverse causality was found. Conclusion Our results illustrate a common genetic architecture, pleiotropic loci, as well as causality between MetS and OA, potentially enhancing our knowledge of high comorbidity and genetic processes that overlap between the 2 disorders.