Physical frailty, genetic risk, mediating biomarkers, and risk of suicide attempt: A prospective cohort study

BACKGROUND: While physical frailty is linked to psychiatric disorders, its association with suicide attempt (SA) risk is unclear. We aimed to investigate the prospective association of physical frailty with SA risk and the modifying and potential mediating roles of genetic risk and blood biomarkers. METHODS AND FINDINGS: This cohort study included 442,920 UK Biobank participants free of SA at baseline. SA events were extracted by linking hospital inpatient records. Physical frailty status was assessed using the five-component Fried phenotype and categorized as nonfrail, prefrail, or frail. Genetic risk for SA was estimated through polygenic risk scores and categorized into high, intermediate, and low risk levels. Cox proportional hazard models were conducted to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the association. Mendelian randomization (MR) analyses were utilized to examine the association between genetically determined physical frailty and SA. Mediation analyses were performed to explore potential biological pathways involving circulating biomarkers. During a median follow-up of 13.6 years, 1,518 (0.3%) individuals developed SA. After multivariable adjustment for sociodemographic characteristics, genetic risk, lifestyle factors, psychiatric disorders, cardiovascular diseases, and cancer, the HRs for SA among those with pre-frailty were 1.61 (95% CI [1.44, 1.80]; P < 0.001) and frailty were 2.16 (95% CI [1.78, 2.61]; P < 0.001) compared with nonfrail individuals. Genetically predicted frailty was also positively associated with SA (odds ratio = 2.06, 95% CI [1.21, 3.52]; P = 0.008). Except for low physical activity, all frailty components were significantly associated with an increased risk of SA (all P < 0.05), with HRs ranging from 1.16 (95% CI [1.01, 1.33]; P = 0.038) to 1.62 (95% CI [1.43, 1.82]; P < 0.001). The additive interaction of physical frailty and genetic risk increased the risk of SA, with the highest risk observed among frail individuals with high genetic risk (HR = 3.09, 95% CI [2.30, 4.17]; P < 0.001), whereas no significant multiplicative interactions were detected. Biomarkers related to liver function, metabolism, immunity, and inflammation may have partially explained this association, accounting for a collective 14.15% (95% CI: 8.94%, 19.74%; P < 0.001) of the total effect, although MR analyses did not support causal mediating effects. The key limitations of this analysis include potential residual confounders and the limited representativeness of the study population. CONCLUSIONS: Pre-frail and frail states were associated with an increased risk of SA, especially among individuals with high genetic risk. Incorporating frailty assessment and management into primary prevention strategies may have implications for SA prevention.