A genome-wide association study of frailty identifies significant genetic correlation with neuropsychiatric, cardiovascular, and inflammation pathways

Abstract

Frailty is an aging-related clinical phenotype defined as a state in which there is an increase in a person's vulnerability for dependency and/or mortality when exposed to a stressor. While underlying mechanisms leading to the occurrence of frailty are complex, the importance of genetic factors has not been fully investigated. We conducted a large-scale genome-wide association study (GWAS) of frailty, as defined by the five criteria (weight loss, exhaustion, physical activity, walking speed, and grip strength) captured in the Fried Frailty Score (FFS), in 386,565 European descent participants enrolled in the UK Biobank (mean age 57 [SD 8] years, 208,481 [54%] females). We identified 37 independent, novel loci associated with the FFS (p < 5 × 10^-8), including seven loci without prior described associations with other traits. The variants associated with FFS were significantly enriched in brain tissues as well as aging-related pathways. Our post-GWAS bioinformatic analyses revealed significant genetic correlations between FFS and cardiovascular-, neurological-, and inflammation-related diseases/traits, and subsequent Mendelian Randomization analyses identified causal associations with chronic pain, obesity, diabetes, education-related traits, joint disorders, and depressive/neurological, metabolic, and respiratory diseases. The GWAS signals were replicated in the Health and Retirement Study (HRS, n = 9,720, mean age 73 [SD 7], 5,582 [57%] females), where the polygenic risk score built from UKB GWAS was significantly associated with the FFS in HRS individuals (OR per SD of the score 1.27, 95% CI 1.22-1.31, p = 1.3 × 10^-11). These results provide new insight into the biology of frailty by comprehensively evaluating its genetic architecture.

Keywords: Aging; Frailty; GWAS; Genetic correlation; Polygenic risk score.

Fig. 1

Manhattan plot of the frailty GWAS in the UK Biobank. Manhattan plot for the discovery GWAS of frailty (n = 386,565). Green dots indicate independent significant leading SNPs that have been reported to be associated with traits other than frailty; Red dots indicate independent significant leading SNPs that have never been reported before

Fig. 2

Replication in the Health and Retirement Study. (a) We plotted the effect sizes of the SNPs identified in the discovery GWAS (UKBB) against their effect sizes in the replication GWAS (HRS). The points represent significant leading SNPs identified in the UKBB. The x-axis and y-axis depict the effect sizes of the SNPs in the UKBB and HRS, respectively. The colored points indicate SNPs that retained significance in the HRS. Specifically, out of the 22 SNPs in the plot, 18 had consistent directions of effects in both studies and three remained significant in HRS. (b) We visualized the association between the frailty phenotype and the frailty PRS in HRS by plotting the mean FFS in 20 groups, which were binned according to the percentile of the frailty PRS in HRS. The PRS was generated using the UKBB data. The plot shows a significant association between the frailty PRS and the frailty phenotype in the HRS cohort, further supporting that the genetic findings from our discovery GWAS are replicable

Fig. 3

Pathway and tissue enrichment. (a) The top 20 pathways associated with frailty were identified using pathway analysis based on our discovery GWAS. The left vertical dotted line represents a P-value of 0.05 for suggestive enrichment and the right vertical dotted line represents the Bonferroni-adjusted P-value for significant enrichment. We found that three pathways were significantly associated with frailty after Bonferroni correction. (b) and (c) show the results from tissue enrichment analysis based on LDSC. Specifically, (b) illustrates the enrichment results across 7 tissues, including brain, muscle, immune, gastrointestinal (GI), epithelium, cardiovascular (CV), and other tissues as annotated using GenoSkyline-Plus annotations. (c) provides a closer look at the stratified enrichment by sub-tissues or cell-types. In both panels (b) and (c), the vertical dotted line represents the Bonferroni-adjusted P-value for significant enrichment. The analysis revealed that brain tissues were significantly associated with frailty

Fig. 4

Mendelian randomization analysis estimates. Effect sizes (beta) and 95% confidence intervals of the associations between FFS and significantly causally associated traits are provided (based on MR-IVW method)