Frailty is a multiply determined state that is associated with poor health outcomes and earlier mortality in older adults. Clinically, it is often measured using the Frailty Index, which creates a graded frailty score based on the number of deficits that co-occur within an individual. We currently lack a genetic phenotype for frailty that accounts for the complex relationships between the numerous traits that define it. This undermines our ability to assess how frailty might interact on a genetic level with other complex traits associated with aging, such as dementia. We used Genomic Structural Equation Modelling (Genomic SEM) to define the shared and trait-specific genetic architecture for well-powered genome-wide association study summary statistics for 30 traits from the Frailty Index. We found that the genetic overlap between these traits can be captured by 6 latent factors, providing novel insights into distinct mechanistic groupings that underlie frailty pathogenesis. These latent genomic factors included those defined by a broad-spectrum of traits linked to generally poor health and unhealthy lifestyle behaviors, as well as factors defined by more specific groupings of items such as cardiometabolic and psychiatric indicators. We subsequently performed a multivariate GWAS of this 6-factor model, which identified genomic risk loci associated with each of the latent factors. We will perform additional post-GWAS analyses to determine what their potential biological relevance might be for aging-related processes. Our findings reflect the first multidimensional genomic analyses of frailty and provide a novel framework for analyzing the shared and unique genetic pathways that commonly occur during aging.
Isabelle F Foote, University of Colorado Boulder
John D Fisk, Dalhousie University, Halifax, Nova Scotia
Tobias K Karakach, Dalhousie University, Halifax, Nova Scotia
Andrew Rutenberg, Dalhousie University, Halifax, Nova Scotia
Kenneth Rockwood, Dalhousie University, Halifax, Nova Scotia
Andrew D Grotzinger, University of Colorado Boulder