eprintid: 10159329 rev_number: 6 eprint_status: archive userid: 699 dir: disk0/10/15/93/29 datestamp: 2022-11-16 10:39:15 lastmod: 2022-11-16 10:39:15 status_changed: 2022-11-16 10:39:15 type: article metadata_visibility: show sword_depositor: 699 creators_name: Atkins, Janice L creators_name: Jylhava, Juulia creators_name: Pedersen, Nancy L creators_name: Magnusson, Patrik K creators_name: Lu, Yi creators_name: Wang, Yunzhang creators_name: Hagg, Sara creators_name: Melzer, David creators_name: Williams, Dylan M creators_name: Pilling, Luke C title: A genome-wide association study of the frailty index highlights brain pathways in ageing ispublished: pub divisions: UCL divisions: B02 divisions: D14 divisions: GA3 divisions: G17 keywords: Science & Technology, Life Sciences & Biomedicine, Cell Biology, Geriatrics & Gerontology, ageing, frailty, frailty index, genetics, UK Biobank, SWEDISH TWIN REGISTRY, BIOBANK, VARIANTS, INSTRUMENTS, SARCOPENIA, RESOURCE, GENES note: © 2021 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. 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. date: 2021-09 date_type: published publisher: WILEY official_url: https://doi.org/10.1111/acel.13459 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1884949 doi: 10.1111/acel.13459 medium: Print-Electronic lyricists_name: Williams, Dylan lyricists_id: DMWIL55 actors_name: Williams, Dylan actors_id: DMWIL55 actors_role: owner funding_acknowledgements: MR/M023095/1 [UK Medical Research Council]; 2015--03255 [Swedish Research Council]; 2018--02077 [Swedish Research Council]; U01-066134 [NIH DK]; [Swedish Foundation for Strategic Research (SSF)]; 20070481 [Heart and Lung foundation]; R01 AG04563 [NIH]; AG10175 [NIH]; AG028555 [NIH]; [MacArthur Foundation Research Network on Successful Aging]; 2009--0795 [Swedish Council for Working Life and Social Research (FAS/FORTE)]; [Strategic Research Program in Epidemiology at Karolinska Institutet]; [Loo & Hans Osterman Foundation]; [Foundation for Geriatric Diseases at Karolinska Institutet] full_text_status: public publication: Aging Cell volume: 20 number: 9 article_number: e13459 pages: 13 event_location: England issn: 1474-9718 citation: Atkins, Janice L; Jylhava, Juulia; Pedersen, Nancy L; Magnusson, Patrik K; Lu, Yi; Wang, Yunzhang; Hagg, Sara; ... Pilling, Luke C; + view all <#> Atkins, Janice L; Jylhava, Juulia; Pedersen, Nancy L; Magnusson, Patrik K; Lu, Yi; Wang, Yunzhang; Hagg, Sara; Melzer, David; Williams, Dylan M; Pilling, Luke C; - view fewer <#> (2021) A genome-wide association study of the frailty index highlights brain pathways in ageing. Aging Cell , 20 (9) , Article e13459. 10.1111/acel.13459 <https://doi.org/10.1111/acel.13459>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10159329/1/A%20genome-wide%20association%20study%20of%20the%20frailty%20index%20highlights%20brain%20pathways%20in%20ageing.pdf