Synergistic impact of 25-hydroxyvitamin D and physical activity on incident depression: Evidence from a prospective cohort and genome-wide data

BACKGROUND: The relationship between 25-hydroxyvitamin D [25(OH)D] levels, physical activity (PA), and depression risk remains underexplored. This study examines how combinations of 25(OH)D and PA influence depression. METHODS: We conducted a longitudinal analysis using data from the English Longitudinal Study of Ageing, including cognitively healthy adults aged 50 years and older at baseline. Baseline measurements of PA and 25(OH)D were taken, with depression as the primary outcome. Multivariate Cox proportional hazards models were used, with and without interaction terms. Furthermore, two-sample Mendelian randomization (MR) analyses were performed. RESULTS: A total of 4146 participants (mean age: 66.0 years; 52.1 % female) were followed for eight years. Multivariate-adjusted hazard ratios (HRs) for depression were 0.71 (95 % CI: 0.61-0.83) for those with high 25(OH)D and PA (P = 0.005), 0.79 (95 % CI: 0.63-0.99) for those younger than 65 (P = 0.042), and 0.65 (95 % CI: 0.53-0.80) for those 65 and older (P = 0.041). A significant interaction between low 25(OH)D and PA was found in the younger group (HR: 1.43, 95 % CI: 1.03-1.99, P = 0.034). High 25(OH)D and PA independently reduced depression risk by 7.2 % and 7.7 %, respectively, with a 23.1 % reduction when combined. Mendelian randomization confirmed these findings. CONCLUSIONS: High 25(OH)D levels are linked to lower depression risk. The combination of high 25(OH)D and PA provides synergistic protection, particularly in older adults, emphasizing the need for vitamin D supplementation and PA in depression prevention.