News | Karolinska Team Identifies New Genes That May Help Prevent Frailty in Older Adults
New research from Sweden’s Karolinska Institutet, published in Nature Aging, is the first to combine large-scale genomic analysis and proteomics to identify several genetic variants associated with frailty in older adults. The findings offer new hope for predicting and addressing age-related functional decline early.
Frailty: An Important Clinical Feature of Aging
Aging is a complex process involving the gradual decline of multiple physiological functions. Frailty is a key clinical feature marked by reduced resilience and greater vulnerability to falls, infection, hospitalization, and death.
There is currently no single gold standard for measuring frailty. The recently developed Hospital Frailty Risk Score (HFRS) is used to identify people at risk. It overlaps with traditional frailty index and frailty phenotype models but places greater emphasis on clinical diagnoses in medical records.
Study Design: Large-Scale Genetic Analysis Across Countries
The team first conducted a genome-wide association study in Finland’s national FinnGen database, which contains genetic and health data from more than 500,000 people, to identify variants associated with frailty. Findings were then validated in the UK Biobank using more than 400,000 genetic samples, with polygenic risk scores (PRS) and meta-analysis used to combine results. Protein-expression and colocalization analyses were also used to identify potential causal genes.
Key Finding: 53 Genetic Variants Associated With Frailty
The study identified 53 significant variants associated with frailty, including 45 reported for the first time. These mapped to 41 genes, 6 of which had not previously been linked to frailty.
Colocalization analysis identified several potential causal genes, including CHST9, C6orf106 (ILRUN), KHK, MET, APOE, CGREF1, and PPP6C.
CHST9: encodes an enzyme important in intercellular signaling
C6orf106 (ILRUN): regulates inflammation and lipid metabolism
CGREF1: associated with the cell cycle and adhesion
APOE: an important gene in Alzheimer’s disease
PPP6C: involved in regulating the NF-κB pathway
Despite their different functions, these genes collectively point to immune and inflammatory regulation, cell interactions, and adhesion as central mechanisms in frailty.
Protein-expression analysis showed that higher CGREF1 and NECTIN2 levels and lower MET and APOC1 levels were associated with greater frailty risk.
Cell-type enrichment analysis found high expression of these genes in several brain regions, including the limbic system, cerebrum, and cerebellum, further highlighting the role of the central nervous system in frailty.
Clinical Significance: New Opportunities for Early Prediction and Intervention
The HFRS-based polygenic risk score effectively predicted frailty, early-onset frailty, mortality, and hospitalization risk. Researchers estimated the heritability of frailty at about 6%, similar to estimates from other methods.
This suggests that identifying high-risk people in midlife through genetic risk scores could support targeted lifestyle changes or interventions to delay or prevent frailty.
Limitations and Outlook
Validation results from the UK Biobank were weaker than those from FinnGen, possibly because of sampling differences: FinnGen includes nationwide cohorts and hospitalized patients, while the UK Biobank primarily consists of volunteers and has a lower overall prevalence of frailty.
Future studies should further examine the roles of immune inflammation and the nervous system in the development of cognitive frailty and advance the clinical use of genetic risk prediction.
News | Karolinska Team Identifies New Genes That May Help Prevent Frailty in Older Adults
News | Karolinska Team Identifies New Genes That May Help Prevent Frailty in Older Adults
New research from Sweden’s Karolinska Institutet, published in Nature Aging, is the first to combine large-scale genomic analysis and proteomics to identify several genetic variants associated with frailty in older adults. The findings offer new hope for predicting and addressing age-related functional decline early.
Frailty: An Important Clinical Feature of Aging
Aging is a complex process involving the gradual decline of multiple physiological functions. Frailty is a key clinical feature marked by reduced resilience and greater vulnerability to falls, infection, hospitalization, and death.
There is currently no single gold standard for measuring frailty. The recently developed Hospital Frailty Risk Score (HFRS) is used to identify people at risk. It overlaps with traditional frailty index and frailty phenotype models but places greater emphasis on clinical diagnoses in medical records.
Study Design: Large-Scale Genetic Analysis Across Countries
The team first conducted a genome-wide association study in Finland’s national FinnGen database, which contains genetic and health data from more than 500,000 people, to identify variants associated with frailty. Findings were then validated in the UK Biobank using more than 400,000 genetic samples, with polygenic risk scores (PRS) and meta-analysis used to combine results. Protein-expression and colocalization analyses were also used to identify potential causal genes.
Key Finding: 53 Genetic Variants Associated With Frailty
The study identified 53 significant variants associated with frailty, including 45 reported for the first time. These mapped to 41 genes, 6 of which had not previously been linked to frailty.
Colocalization analysis identified several potential causal genes, including CHST9, C6orf106 (ILRUN), KHK, MET, APOE, CGREF1, and PPP6C.
CHST9: encodes an enzyme important in intercellular signaling
C6orf106 (ILRUN): regulates inflammation and lipid metabolism
CGREF1: associated with the cell cycle and adhesion
APOE: an important gene in Alzheimer’s disease
PPP6C: involved in regulating the NF-κB pathway
Despite their different functions, these genes collectively point to immune and inflammatory regulation, cell interactions, and adhesion as central mechanisms in frailty.
Protein-expression analysis showed that higher CGREF1 and NECTIN2 levels and lower MET and APOC1 levels were associated with greater frailty risk.
Cell-type enrichment analysis found high expression of these genes in several brain regions, including the limbic system, cerebrum, and cerebellum, further highlighting the role of the central nervous system in frailty.
Clinical Significance: New Opportunities for Early Prediction and Intervention
The HFRS-based polygenic risk score effectively predicted frailty, early-onset frailty, mortality, and hospitalization risk. Researchers estimated the heritability of frailty at about 6%, similar to estimates from other methods.
This suggests that identifying high-risk people in midlife through genetic risk scores could support targeted lifestyle changes or interventions to delay or prevent frailty.
Limitations and Outlook
Validation results from the UK Biobank were weaker than those from FinnGen, possibly because of sampling differences: FinnGen includes nationwide cohorts and hospitalized patients, while the UK Biobank primarily consists of volunteers and has a lower overall prevalence of frailty.
Future studies should further examine the roles of immune inflammation and the nervous system in the development of cognitive frailty and advance the clinical use of genetic risk prediction.
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