Aging is a highly complex process with substantial heterogeneity in health trajectories between individuals. Frailty is a condition in which the body loses its resilience and becomes more vulnerable to falls, infections, and other stresses, with heightened frailty contributing to the risk of hospitalization and death. Understanding the differential impact of frailty across individuals is valuable for the development of aging-related therapies.
In a new study published in Nature Aging titled, “Large-scale genome-wide analyses with proteomics integration reveal novel loci and biological insights into frailty,” researchers from Karolinska Institutet in Stockholm have found genetic variants linked to frailty after completing a comprehensive genetic analysis of nearly one million people in Finland and the U.K. Results identified 53 independent lead variants associated with frailty, of which 45 were novel and not previously reported in the genome-wide association study (GWAS) catalog.
”Our results show that frailty is not caused by a single factor, but by many genes that affect how our immune system, brain, and metabolism work. Some of these genes are completely new discoveries,” stated Juulia Jylhävä, PhD, associate professor at the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet and corresponding author of the study.
The authors defined frailty using the Hospital Frailty Risk Score (HFRS), which is based on 109 weighted International Classification of Diseases, a World Health Organization (WHO) published system for classifying and coding diseases, health conditions, and external causes of injury. The HFRS characterizes older adults with high resource use and diagnoses associated with frailty. To date, no previous studies into the genetics of frailty using the HFRS exist.
A GWAS study was conducted in FinnGen, a public-private partnership that has collected and analyzed genomes and health data from over 500,000 Finnish biobank donors to understand the genetic basis of diseases. The results were also replicated in the UK Biobank, with a sample size of over 400,000 genomes, both at the individual variant level and through polygenic risk scores.
Genes were prioritized through colocalization with expression, splicing, and protein quantitative trait loci and proteomics integration. Colocalization analysis supported a causal role for several genes, including cell growth regulator with EF-hand domain 1 (CGREF1), a protein-coding gene involved in cell growth, proliferation, and signaling pathways, apolipoprotein E (APOE), a gene strongly linked to the risk of Alzheimer’s disease, and PPP6C, a gene encoding a serine/threonine phosphatase, which plays a key role in cell cycle regulation, autophagy, and innate immunity. The researchers meta-analyzed the results from both GWAS studies to provide further validation of the results.
The study provides further support for the role of immunoinflammatory and nervous system functions in the etiology of frailty. Looking ahead, the study’s genetic insights offer a foundation to better identify frailty risk across individuals for age-related health treatment. Future studies will explore the role of these functions in the development of cognitive frailty.
“In the future, we may be able to identify people who are at risk as early as middle age, when there is still time to prevent frailty. This opens the door to new ways of improving health in older people,” said Jylhävä.