BMI mediates the causal relationship between depression and the risk of Rheumatoid arthritis: The results from NHANES 2003 to 2018 and the Mendelian studies

Depression and rheumatoid arthritis (RA) frequently coexist, leading to significantly impaired quality of life and increased healthcare costs. However, the causal relationship between these 2 conditions remains unclear. This study aimed to assess the causal association between depression and RA and to explore the mediating role of body mass index (BMI). We analyzed data from the National Health and Nutrition Examination Survey 2003 to 2018 using weighted multivariable-adjusted logistic regression to examine the association between depression and RA. Additionally, Mendelian randomization (MR) analyses, based on summary statistics from genome-wide association studies, were conducted to investigate the causal relationship. A 2-step MR analysis further evaluated the mediation effect of BMI. Observational analysis of National Health and Nutrition Examination Survey data showed a significant positive association between depression and RA risk (odds ratio [OR] = 1.25; 95% confidence interval [CI], 1.01-1.54). Higher depression scores were similarly associated with increased RA risk (OR = 1.02; 95% CI, 1.01-1.03). MR analysis provided genetic evidence supporting the causal link between depression and RA (OR = 4.61; 95% CI, 1.17-18.17). BMI partially mediated this causal relationship (mediation effect = 0.085), explaining 5.6% of the association. Our findings indicate a causal relationship between depression and an increased risk of RA, supported by both observational and genetic evidence. BMI plays a modest mediating role in this association.