Large-scale genome-wide analyses with proteomics integration reveal novel loci and biological insights into frailty

Frailty is a clinically relevant phenotype with significant gaps in our understanding of its etiology. We performed a genome-wide association study of frailty in FinnGen (N=500,737) and replicated the signals in the UK Biobank (N=429,463) using polygenic risk scores (PRSs). We prioritized genes through proteomics integration (N∼45,000; UK Biobank) and colocalization of protein quantitative trait loci. Frailty was measured using the Hospital Frailty Risk Score (HFRS). We observed 1,588 variants associated with frailty ( p <5×10 ^-8 ) of which 1,242 were novel, i.e., previously unreported for any trait. The associations mapped to 106 genes of which 31 were novel. PRS replication validated the signals (β=0.074, p <2×10 ^-16 ). Cell type enrichment analysis indicated expression in neuronal cells. Protein levels of KHK , CGREF1 , MET , ATXN2 , ALDH2 , NECTIN2 , APOC1 , APOE and FOSB were associated with HFRS, whereas colocalized signals were observed within APOE and BRAP . Our results reveal novel genetic contributions and causal candidate genes for frailty.