Genome-Wide Cox Regression Analysis Identifies 134 Novel Risk Loci for Disability Development: The Canadian Longitudinal Study on Aging and UK Biobank

Abstract Background Disability significantly affects the well-being of older adults and imposes substantial personal and social burdens. Although genetic effects play a role in disability, large-scale genome-wide association studies (GWAS) of disability development remain scarce. Methods We performed the first Cox proportional hazards GWAS on disability development on 8,421 individuals aged 65 and older from the Canadian Longitudinal Study on Aging (CLSA). Disability was defined as the inability to perform daily activities, as measured by the Activities of Daily Living (ADL) scale. A polygenic hazard score (PHS) was developed and incorporated into the predictive model, along with demographic and environmental factors. Results The study observed a 16.28% incidence of disability over a mean follow-up duration of 4.64 years (SD = 1.95). The COX-GWAS identified six genome-wide significant variants (p < 5E-08) and 134 independent SNPs with suggestive significance level (p < 1E−05). Replication in the UK Biobank confirmed that rs589819, rs56294014, and rs143714258 remained nominally significant and exhibited consistent effect directions. Post-GWAS analyses, including transcriptome-wide association studies TWAS, gene set, and tissue enrichment analyses, revealed genetic pathways related to inflammation regulation, neurogenesis, and metabolic processes. Incorporating PHS with demographic and environmental factors improves the prediction performance in both CLSA and UKB. Conclusion This study is among the first genome-wide Cox regression analyses to uncover novel genetic loci and biological pathways involved in disability development in older adults. These findings provide a foundation for predictive modeling and targeted prevention strategies.