Discovery of frailty-linked proteins through multi-omics integration of brain and plasma proteomes with GWAS datasets

Frailty, a clinical state of increased vulnerability to stressors with aging, imposes significant strain on healthcare systems. Its genetic underpinnings remain incompletely explored, highlighting the need to identify novel therapeutic targets for aging. We integrated brain ( N = 376) and plasma ( N = 35,559) proteomes with a large-scale GWAS of Fried Frailty Score in 386,565 UK Biobank participants. We employed a combined analysis using Mendelian randomization (MR), Steiger filtering, Bayesian colocalization, proteome-wide (PWAS), and transcriptome-wide (TWAS) association studies. Multi-method integration identified CISD2 in the brain (supported by PWAS, TWAS, MR, colocalization) and MST1 in plasma (supported by PWAS, MR, colocalization, SMR) as high-confidence associations. GMPPB and GPX1 (brain), and FCGR3A and HEXIM1 (plasma) showed moderate confidence. Other candidates (e.g., TMEM106B, NT5DC3, RMDN3, MXRA7, EGFR, NLGN, NEGR1, ACAA1) had lower support. Western blot confirmed increased CISD2 expression in brains of aging-prone SAMP8 mice versus controls (SAMR1). MST1 protein was elevated in SAMP8 heart, liver, and spleen, and its mRNA increased in SAMP8 plasma. Our study identifies CISD2 and MST1 as high-confidence proteins implicated in frailty pathogenesis through brain and plasma mechanisms, respectively. These findings provide crucial molecular insights into aging and highlight promising targets for therapeutic intervention to mitigate frailty. • CISD2 (brain) and MST1 (plasma) are high-confidence frailty-associated proteins identified by integrative multi-omics. • CISD2 is prioritized as a brain-specific driver, while MST1 acts as a systemic plasma-derived risk factor. • Mendelian randomization, Bayesian colocalization, and animal validation provide robust evidence for both proteins. • Elevated CISD2 in SAMP8 brain and MST1 in heart, liver, spleen, plasma confirm roles in accelerated aging. • The study establishes a brain-periphery axis of frailty, offering new biomarkers and therapeutic targets.