Behavioural Brain Research · Jun 18, 2025
The shared genetic structure and causal analysis between frailty and suicide
By Deng S, Qian L, Fang L
BACKGROUND: Frailty is associated with decreased physiological reserves, loss of independence, and depression, and may be particularly relevant for identifying elderly individuals at increased risk for suicide attempts. However, the relationship between frailty and suicide attempt risk remains unclear, and the underlying mechanisms linking the two are still insufficiently explored. METHODS: Using data obtained from genome-wide association study (GWAS) summaries, we employed linkage disequilibrium score regression (LDSC) to determine the genetic correlation between frailty and suicide. To visualize the cross-trait genetic enrichment between suicide and FI, we constructed conditional quantile-quantile (Q-Q) plots. Causal relationships were established using two-sample Mendelian randomization. We conducted a gene-based multivariate analysis (MAGMA) to examine the enrichment of single nucleotide polymorphisms (SNPs) across various tissue types. RESULTS: There is a significant positive genetic correlation between frailty and suicide (rg = 0.35, p = 5.74E-21). Mendelian randomization revealed a causal relationship between the genetic susceptibility of frailty and suicide (OR, 1.77; 95 % CI: 1.37-2.31; p = 1.72E-05). The genetic correlation between frailty and suicide showed significant enrichment in both the cerebellar hemispheres and the cerebellum. LIMITATIONS: One limitation of this study is that it relies on summary-level GWAS data, which may not capture individual-level heterogeneity or account for potential confounders in the frailty-suicide relationship. CONCLUSION: There is a genetic correlation and causal relationship between frailty and suicide, and this relationship may be mediated by the cerebellum. These findings contribute to a deeper understanding of their pathogenesis and could aid in identifying potential therapeutic targets and early screening strategies.