Testing bidirectional associations of major depressive disorder with medical conditions: two-sample Mendelian...

Depression is associated with increased risk for a variety of medical conditions. However, the extent to which these associations reflect a causal impact of depression on medical conditions, or vice-versa, remains unresolved. We tested bidirectional causal relationships between major depressive disorder (MDD) and multiple medical conditions and symptoms, using a genetically-informed approach for causal inference. Candidate disease traits were selected based on their genetic associations with MDD, as identified in prior phenome-wide association studies that used polygenic scores for MDD and electronic health records for trait ascertainment. In total, 183 candidate traits across 15 phenome-wide association study code (phecode) categories were identified. We conducted bidirectional, two-sample Mendelian randomization using summary statistics from non-overlapping, European-ancestry genome-wide association studies (GWASs) of MDD and the disease traits. There were sufficient instrumental genetic variables to test causal effects of MDD on 182 of these traits. Genetic liability to MDD was associated with 109 (59.9%) traits, with the strongest potential causal evidence observed for 105 (57.7%) traits across 13 phecode categories: Mental disorders; digestive, genitourinary, neurological, respiratory, circulatory-system, endocrine/metabolic, musculoskeletal, sense-organ, infectious-disease, and dermatologic conditions; injuries and poisonings; and symptoms. There were 10 disease traits with sufficient instrumental genetic variables to test causal effects on MDD. Of these 10 traits, only two (20.0%)-genetically-predicted gastroesophageal reflux disease (GERD) and hypertension-were associated with MDD risk. GERD showed evidence of bidirectional associations with MDD (MDD → GERD: odds ratio (OR) = 2.02, 99% confidence interval [CI] 1.84-2.22; GERD → MDD: OR = 1.48, 99% CI 1.39-1.58). The present results are consistent with a causal effect of major depressive disorder on a broad range of medical conditions and symptoms. Prevention and treatment of MDD could benefit not only mental health but also physical health.