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<5x10-8) 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<2x10-16). 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.