{"doi":"10.1111/acel.13459","title":"A genome‐wide association study of the frailty index highlights brain pathways in ageing","abstract":"Abstract Frailty is a common geriatric syndrome and strongly associated with disability, mortality and hospitalization. Frailty is commonly measured using the frailty index (FI), based on the accumulation of a number of health deficits during the life course. The mechanisms underlying FI are multifactorial and not well understood, but a genetic basis has been suggested with heritability estimates between 30 and 45%. Understanding the genetic determinants and biological mechanisms underpinning FI may help to delay or even prevent frailty. We performed a genome‐wide association study (GWAS) meta‐analysis of a frailty index in European descent UK Biobank participants ( n = 164,610, 60–70 years) and Swedish TwinGene participants ( n = 10,616, 41–87 years). FI calculation was based on 49 or 44 self‐reported items on symptoms, disabilities and diagnosed diseases for UK Biobank and TwinGene, respectively. 14 loci were associated with the FI ( p < 5*10 −8 ). Many FI‐associated loci have established associations with traits such as body mass index, cardiovascular disease, smoking, HLA proteins, depression and neuroticism; however, one appears to be novel. The estimated single nucleotide polymorphism (SNP) heritability of the FI was 11% (0.11, SE 0.005). In enrichment analysis, genes expressed in the frontal cortex and hippocampus were significantly downregulated (adjusted p < 0.05). We also used Mendelian randomization to identify modifiable traits and exposures that may affect frailty risk, with a higher educational attainment genetic risk score being associated with a lower degree of frailty. Risk of frailty is influenced by many genetic factors, including well‐known disease risk factors and mental health, with particular emphasis on pathways in the brain.","journal":"Aging Cell","year":2021,"id":145726,"datarank":0.8684940256345881,"base_score":5.7899601708972535,"endowment":5.7899601708972535,"self_citation_contribution":0.8684940256345881,"citation_network_contribution":0.0,"self_endowment_contribution":0.8684940256345881,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":326,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9621,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":228609,"name":"Juulia Jylhävä","orcid":"0000-0003-0250-4491","position":1,"is_corresponding":false},{"id":5347,"name":"Nancy L. Pedersen","orcid":"0000-0001-8057-3543","position":2,"is_corresponding":false},{"id":5393,"name":"Patrik K. E. Magnusson","orcid":"0000-0002-7315-7899","position":3,"is_corresponding":false},{"id":347010,"name":"Yi Lu","orcid":"0000-0001-9933-3654","position":4,"is_corresponding":false},{"id":228606,"name":"Yunzhang Wang","orcid":"0000-0003-1165-3595","position":5,"is_corresponding":false},{"id":228610,"name":"Sara Hägg","orcid":"0000-0002-2452-1500","position":6,"is_corresponding":false},{"id":230637,"name":"David Melzer","orcid":"0000-0002-0170-3838","position":7,"is_corresponding":false},{"id":618629,"name":"Dylan M. Williams","orcid":"0000-0002-3825-2487","position":8,"is_corresponding":false},{"id":230633,"name":"Luke C. Pilling","orcid":"0000-0002-3332-8454","position":9,"is_corresponding":false},{"id":230634,"name":"Janice L. Atkins","orcid":"0000-0003-4919-9068","position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:42:12.871665Z","pmid":"34431594","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}