Abstract
BACKGROUND: Intrinsic capacity (IC) is a multidimensional concept within the World Health Organization framework for healthy aging. It refers to the composite of an individual's physical and mental capacities that enable them to maintain well-being, functional ability, and engagement in valued activities throughout life. While substantial evidence supports the biological basis of IC and its subdomains, the extent to which genetic factors influence IC remains largely unexplored, with no studies currently available. METHODS: Using datasets from the UK Biobank (UKB; N = 44 631) and the Canadian Longitudinal Study on Aging (CLSA; N = 13 085), we implemented the restricted maximum likelihood method to estimate SNP-based heritability (h2snp), followed by a Genome-Wide Association Study (GWAS) to identify genetic variants associated with IC, and post-GWAS analyses to pinpoint biological implications. RESULTS: The h2snp for IC was estimated at 25.2% in UKB and 19.5% in CLSA. Our GWAS identified 38 independent SNPs for IC across 10 genomic loci and 4289 candidate SNPs, mapped to 197 genes. Post-GWAS analysis revealed the role of these genes in cellular processes such as cell proliferation, immune function, metabolism, and neurodegeneration, with high expression in muscle, heart, brain, adipose, and nerve tissues. Of the 52 traits tested, 23 showed significant genetic correlations with IC, and a higher genetic loading for IC was associated with higher IC scores. CONCLUSIONS: Overall, this study provides comprehensive evidence on the genetic architecture of IC, identifying novel genetic variants and biological pathways, advancing our current knowledge and laying the foundation for ongoing and future research on healthy aging.