Genome-Wide Crossover Analysis Identification of Shared Genetic Effect Site between Frailty and Multiple Psychiatric Disorders

Frailty, a geriatric syndrome marked by reduced physiological reserves, shares significant biological and pathological mechanisms with psychiatric disorders such as depression, anxiety, and sleep disorders, yet their shared genetic underpinnings remain poorly understood. This study aimed to elucidate the genetic correlations and pleiotropic mechanisms linking frailty with these psychiatric conditions by leveraging genome-wide association study (GWAS) summary statistics and advanced cross-trait pleiotropy analyses. A total of 748 pleiotropic single-nucleotide polymorphisms (SNPs) were identified, with 36 loci confirmed as dominant risk factors and 20 validated through causal co-localization analysis. Gene-level analyses pinpointed key pleiotropic genes (e.g., TTC12, TMOD2, and AMT), and pathway enrichment analyses revealed significant involvement of synaptic plasticity, arginine metabolism, and complement24 dependent cytotoxicity regulation. Tissue-specific enrichment highlighted the hypothalamus, frontal cortex, and pituitary as critical sites, while immune co26 localization analyses implicated B cells, dendritic cells, and myeloid subsets in disease mediation. These findings underscore the shared genetic and immune regulatory mechanisms underlying frailty and psychiatric disorders, providing novel insights into their interconnected pathophysiology and identifying potential therapeutic targets. This study not only bridges critical gaps in the understanding of these conditions but also offers a foundation for precision medicine strategies to improve clinical outcomes in aging populations.