Associations of Depression and Antidepressant Use with the Risk of Tuberculosis Sequelae: Insight from Genetic...

Background: Depression and antidepressant use have been suggested to be associated with tuberculosis sequelae, but whether these associations are causal remains unclear. We aimed to investigate the potential associations of genetically predicted depression and antidepressant use with the risk of tuberculosis sequelae using a two-sample Mendelian randomization (MR) study. Methods: Summary statistics for depression (13,559 cases and 435,855 controls), antidepressant use (33,757 cases and 270,405 controls), and tuberculosis sequelae (727 cases and 497,160 controls) were extracted from large-scale genome-wide association studies of European-ancestry participants. MR estimates were generated using the inverse-variance weighted (IVW) method in the main analysis with a series of sensitivity analyses. Results: In the primary fixed-effects IVW analysis, genetically predicted depression showed suggestive evidence of an association with an increased risk of tuberculosis sequelae (OR = 1.218, 95% CI: 1.003-1.480, p = 0.047), whereas genetically predicted antidepressant use showed suggestive evidence of an inverse association with the risk of tuberculosis sequelae (OR = 0.692, 95% CI: 0.497-0.964, p = 0.029). Both primary estimates provided suggestive evidence of associations, although they did not meet the Bonferroni-corrected significance threshold of p < 0.025. In the multiplicative random-effects IVW sensitivity analyses, the effect directions remained unchanged although statistical significance was not retained, while other complementary sensitivity analyses generally yielded directionally consistent estimates. Conclusions: Our findings provide novel, hypothesis-generating genetic evidence that genetically predicted depression and antidepressant use may be associated with the risk of tuberculosis sequelae. These findings highlight potentially important links between mental health-related factors and long-term tuberculosis outcomes and warrant further validation in independent studies.