Causal Relationships Between Social Isolation and Osteoarthritis: A Mendelian Randomization Study in European Population

Objective: We aimed to investigate the causal relationships between social isolation and osteoarthritis. Methods: Publicly available genome-wide association study (GWAS) summary statistics of social isolation and osteoarthritis in European population were obtained from the Neale lab Consortium and the Medical Research Council-Integrative Epidemiology Unit (MRC-IEU) consortium, respectively. Single nucleotide polymorphisms (SNPs) associated with the traits were identified by P < 5x10(-8) and linkage disequilibrium r(2) < 0.1. Three Mendelian randomization (MR) methods including the inverse-variance weighted (IVW) method, weighted median estimator, and MR-Egger regression were used to assess the potential causal effect of social isolation on osteoarthritis and the potential causal effect of osteoarthritis on social isolation. Leave-one-out analysis and test of directional horizontal pleiotropy via MR-Egger regression were performed as sensitivity analyses. Results: When evaluating the causal effect of social isolation on osteoarthritis, five SNPs (rs12364432, rs13291079, rs2352075, rs4958586, rs599550) significantly associated with social isolation were studied as instruments, and social isolation was found to be causally associated with increased risk of osteoarthritis (odds ratio [OR] 1.197 (95% confidence interval (CI) 1.096-1.308) estimated by the IVW method). When evaluating the causal effect of osteoarthritis on social isolation, six SNPs (rs10405617, rs12133235, rs13107325, rs2290573, rs3771501, rs75621460) significantly associated with osteoarthritis were studied as instruments but no causal effect of osteoarthritis on social isolation was found (OR 1.104 (95% CI 0.887-1.375) estimated by the IVW method). Consistent causal relationships were observed when estimated by the weighted median estimator and MR-Egger regression. Leave-one-out analysis and test of directional horizontal pleiotropy suggested the robustness of the above findings. Conclusion: Social isolation is causally associated with osteoarthritis, and further work is needed to investigate the potential mechanisms.