Bidirectional causal relational between frailty and mental illness: a two-sample Mendelian randomization study

Frailty has been associated with mental illness (MI) observational studies, but the causal relationship between these factors remains uncertain. We aimed to assess the bidirectional causality between frailty and MI by two-sample Mendelian randomization (MR) analyses.To investigate the causal relationship among them, summary statistics of frailty index (FI) and six types of MI: anxiety, depression, affective disorder, mania, schizophrenia, and obsessive-compulsive disorder (OCD) were included in this MR study. This MR analysis was performed using inverse variance weighting (IVW), MR-Egger regression, and weighted median. The stability of the results was evaluated using Cochran’s Q test, MR-Egger intercept test, Funnel Plots, and leave-one-out analysis.Genetic predisposition to FI was significantly associated with increased anxiety (odds ratio [OR] = 1.62, 95% confidence interval [CI] 1.13-2.33, P = 8.18E-03), depression (OR = 1.88, 95% CI 1.30-2.71, P = 8.21E-04), affective disorder (OR = 1.70, 95% CI 1.28-2.27, P = 2.57E-04). However, our study findings do not demonstrate a causal relationship between FI and mania (OR = 1.02, 95% CI 0.99-1.06, P = 2.20E-01), schizophrenia (OR = 1.02, 95% CI 0.07-0.86, P = 9.28E-01). In particular, although the IVW results suggest a potential causal relationship between FI and OCD (OR = 0.64, 95% CI 0.07-0.86, P = 2.85E-02), the directions obtained from the three methods we employed ultimately show inconsistency. Therefore, the result must be interpreted with caution. The results of the reverse MR analysis indicated a statistically significant and causal relationship between anxiety (OR = 1.06, 95% CI 1.01-1.11, P = 2.00E-02), depression (OR = 1.14, 95% CI 1.04-1.26, P = 7.99E-03), affective disorder (OR = 1.15, 95% CI 1.09-1.21, P = 3.39E-07), and schizophrenia (OR = 1.02, 95% CI 1.01-1.04, P = 1.70E-03) with FI. However, our findings do not provide support for a link between mania (OR = 1.46, 95% CI 0.79-2.72, P = 2.27E-01), OCD (OR = 1.01, 95% CI 1.00-1.02, P = 2.11E-01) and an increased risk of FI.The MR results suggest a potential bidirectional causal relationship between FI and anxiety, depression, and affective disorder. Schizophrenia was found to be associated with a higher risk of FI. The evidence was insufficient to support a causal relationship between Fl and other Ml. These findings offer new insights into the development of effective management strategies for frailty and MI.