Assessment of Bidirectional Relationships between Frailty and Mental Disorders: A Bidirectional Mendelian Randomization Study

Abstract

Objectives: Although observational studies have reported the association between frailty and mental disorders, the causality remains unclear. We aimed to evaluate the bidirectional causal association between frailty levels and mental disorders using a 2-sample Mendelian randomization (MR) analysis.

Design: A bidirectional, 2-sample Mendelian randomization (MR) analysis.

Setting and participants: Instrumental variables were obtained from large-scale genome-wide association study (GWAS) of a European-descent population for frailty index (FI, n = 175,226), Fried Frailty Score (FFS, n = 386,565), major depressive disorder (MDD, n = 674,452), bipolar disorder (n = 353,899), anxiety and stress-related disorder (ASRD, n = 31,880), and schizophrenia (n = 127,906).

Methods: Two-sample MR analyses were conducted using inverse variance-weighted method, with sensitivity analyses using MR-Egger, weighted median, and simple median methods.

Results: Per SD increase in genetically predicted FI and FFS increased the risk of MDD [odds ratio (OR) 1.56, 95% CI 1.27-1.94, P = 3.65 × 10^-5, and OR 1.67, 95% CI 1.26-2.20, P = 3.02 × 10^-4, respectively]. Per-SD increase in genetically predicted FI also increased the risk of ASRD (OR 2.76, 95% CI 1.36-5.60, P = .005). No significant effect was observed for frailty levels on the risk of bipolar disorder and schizophrenia. In the reverse direction, genetically predicted MDD was associated with higher FI (β 0.182, 95% CI 0.087-0.277, P = 1.79 × 10^-4) and FFS (β 0.121, 95% CI 0.087-0.155, P = 4.43 × 10^-12). No reliable evidence supported the effects of genetically predicted bipolar disorder, ASRD, or schizophrenia on frailty levels.

Conclusions and implications: A bidirectionally causal association exists between frailty levels and MDD, and higher FI is associated with a higher risk of ASRD. No reliable evidence suggested the causal associations of other mental disorders with frailty. Our findings provided evidence for introduction of psychological-related strategies in management of frailty.

Keywords: Frailty; Mendelian randomization; anxiety and stress-related disorder; bipolar disorder; major depressive disorder; mental disorder; schizophrenia.