Association Between Rheumatoid Arthritis and Osteoporosis in Japanese Populations: A Mendelian Randomization Study

The positive association between rheumatoid arthritis (RA) and osteoporosis has been reported in previous observational studies, but the causal relationship remains unclear. This study was undertaken to investigate whether RA was causally associated with osteoporosis in Japanese populations using Mendelian randomization (MR) analyses.Publicly available summarized data from genome-wide association studies (GWAS) on RA (4,199 cases and 208,254 controls) and osteoporosis (7,788 cases and 204,665 controls) were obtained from BioBank Japan. Eleven RA-related single-nucleotide polymorphisms (P < 5×10-8 ) were selected as instrumental variables. We used the inverse variance-weighted method as the primary method to calculate the odds ratios (ORs) and 95% confidence intervals (95% CIs). We also used the MR-Egger's method, weighted median, and weighted mode to determine the robustness of the main results. To partially test the horizontal pleiotropy, we used the MR-Egger's intercept test and the Mendelian randomization pleiotropy residual sum and outlier (MRPRESSO) test.Using the inverse variance-weighted method, we showed that genetically predicted RA was positively associated with osteoporosis (OR 1.10, 95% CI 1.06-1.14, P < 0.001). The positive association was robust when we tested the results using the MR-Egger's method (OR 1.09, 95% CI 1.03-1.16, P = 0.023), weighted median (OR 1.09, 95% CI 1.04-1.15, P < 0.001), and weighted mode (OR 1.08, 95% CI 1.03-1.13, P = 0.012). Horizontal pleiotropy was not detected (P = 0.737) by the MR-Egger's intercept test or the MRPRESSO test.Our results show a potential causal association between genetically predicted RA and osteoporosis. The finding was consistent when we used different MR methods and the sensitivity analysis. Further MR studies are needed when GWAS with more details of RA and osteoporosis performed in other East Asian/Japanese populations are available.