Abstract
BACKGROUND: An increasing number of observational studies have reported associations between frailty and mental disorders, but the causality remains ambiguous. AIMS: To assess the bidirectional causal relationship between frailty and nine mental disorders. METHOD: We conducted a bidirectional two-sample Mendelian randomisation on genome-wide association study summary data, to investigate causality between frailty and nine mental disorders. Causal effects were primarily estimated using inverse variance weighted method. Several secondary analyses were applied to verify the results. Cochran's Q-test and Mendelian randomisation Egger intercept were applied to evaluate heterogeneity and pleiotropy. RESULTS: Genetically determined frailty was significantly associated with increased risk of major depressive disorder (MDD) (odds ratio 1.86, 95% CI 1.36-2.53, P = 8.1 × 10(-5)), anxiety (odds ratio 2.76, 95% CI 1.56-4.90, P = 5.0 × 10(-4)), post-traumatic stress disorder (PTSD) (odds ratio 2.56, 95% CI 1.69-3.87, P = 9.9 × 10(-6)), neuroticism (β = 0.25, 95% CI 0.11-0.38, P = 3.3 × 10(-4)) and insomnia (β = 0.50, 95% CI 0.25-0.75, P = 1.1 × 10(-4)). Conversely, genetic liability to MDD, neuroticism, insomnia and suicide attempt significantly increased risk of frailty (MDD: β = 0.071, 95% CI 0.033-0.110, P = 2.8 × 10(-4); neuroticism: β = 0.269, 95% CI 0.173-0.365, P = 3.4 × 10(-8); insomnia: β = 0.160, 95% CI 0.141-0.179, P = 3.2 × 10(-61); suicide attempt: β = 0.056, 95% CI 0.029-0.084, P = 3.4 × 10(-5)). There was a suggestive detrimental association of frailty on suicide attempt and an inverse relationship of subjective well-being on frailty. CONCLUSIONS: Our findings show bidirectional causal associations between frailty and MDD, insomnia and neuroticism. Additionally, higher frailty levels are associated with anxiety and PTSD, and suicide attempts are correlated with increased frailty. Understanding these associations is crucial for the effective management of frailty and improvement of mental disorders.