Assessment of the bidirectional causal association between frailty and depression: A Mendelian randomization study

Observational studies have demonstrated a strong bidirectional association between frailty and depression, but it remains unclear whether this association reflects causality. This study aimed to examine the bidirectional causal relationship between frailty and depression.Using genome-wide association study summary data, two-sample Mendelian randomization was performed to test for the potential bidirectional causality between frailty, as defined by both the frailty index and the frailty phenotype, and depression. Several frailty-related traits were additionally investigated, including weaker hand grip strength, slower walking pace and physical inactivity. Findings were replicated using an independent depression data source and verified using multiple sensitivity analyses.Genetically predicted higher frailty index (odds ratio [OR], 1.86; P < 0.001), higher frailty phenotype score (OR, 2.79; P < 0.001), lower grip strength (OR, 1.23; P = 0.003), slower walking pace (OR, 1.55; P = 0.027) and physical inactivity (OR, 1.44; P = 0.003) all were associated with a higher risk of depression. As for the reverse direction, genetic liability to depression showed consistent associations with a higher frailty index (beta, 0.167; P < 0.001) and a higher frailty phenotype score (beta, 0.067; P = 0.001), but not with other frailty-related traits that were investigated. The results were stable across sensitivity analyses and across depression datasets.Our findings add novel evidence supporting the bidirectional causal association between frailty and depression. Improving balance and muscle strength and increasing physical activity may be beneficial in both depression and frailty.