Uncovering the multivariate genetic architecture of frailty with genomic structural equation modelling

Frailty is a multifaceted clinical state associated with accelerated aging and adverse health outcomes. Informed etiological models of frailty hold promise for producing widespread health improvements across the aging population. Frailty is currently measured using aggregate scores, which obscure etiological pathways that are only relevant to subcomponents of frailty. Therefore, we performed the first multivariate genome-wide association study of the latent genetic architecture between 30 frailty deficits, which identified 408 genomic risk loci. Our model included a general factor of genetic overlap across all deficits, plus six novel factors indexing shared genetic signal across specific groups of deficits. Follow-up analyses demonstrated the added clinical and etiological value of the six factors, including predicting frailty in external datasets, divergent genetic correlations with clinically relevant outcomes, and unique underlying biology linked to aging. This suggests nuanced models of frailty are key to understanding its causes and how it relates to worse health.