177 genome-wide association analysis of the frailty phenotype in uk biobank highlights cardiometabolic and autoimmune signatures in ageing

Abstract Background Frailty is a state of advanced biological age that is characterized by multisystem physiological decline and advanced risk to adverse health outcomes. One approach to defining frailty is using the Fried frailty phenotype, a five-point list of health-related criteria used to score individuals as non-frail, pre-frail, or frail. The biological basis of frailty is not fully understood, nor why some experience frailty at younger ages. Between 30%-45% of frailty risk is estimated to be genetic. This study aimed to investigate the genetic basis of frailty phenotype risk using data from UK Biobank. Methods UK Biobank is a large-scale biomedical database of community dwelling adults (n = 502,529, age range: 37-73 years, 54% female). UK Biobank has genome-wide genotyping (approx. 93 million variants), health, and demographic data for all participants. A genome-wide association study (GWAS) of the frailty phenotype was performed on British and Irish adults aged 60 to 70 years (n = 157,720) to identify heritable factors which predict frailty progression in later life. Functional mapping was performed to determine genes and biological pathways enriched in GWAS results. Results 95 single nucleotide polymorphisms (SNPs) from three independent genomic risk loci were significantly associated (p < 5e-8) with the frailty phenotype in UK Biobank participants. Three genes, PPP1R3A, LONRF2, and AIF1 were statistically enriched with genetic variants. Tissue-specific expression analysis indicated genes differentially expressed in blood vessels were enriched. Linkage Disequilibrium Score Regression (lambda = 1.2005, intercept = 1.0006) indicated GWAS test statistic inflation resulting from polygenicity. SNP-based heritability was estimated to be 6.34% (SE: 0.36%). Conclusion SNP-based heritability of the frailty phenotype was lower than expected in comparison to previous reports of 30%-45%. Statistically significant genomic risk loci, genes, and tissue-enrichment pointed towards dysregulation of cardiometabolic, cardiovascular, and immunological processes in frailty risk, contrasting to brain pathways enriched in previous genomic analyses of the frailty index.