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| PMID |
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| TITLE |
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| Uncovering the multivariate genetic architecture of frailty with genomic structural equation modeling. |
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| ABSTRACT |
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| Frailty is a multifaceted clinical state associated with accelerated aging and adverse health outcomes. Informed etiological models of frailty hold promise for producing widespread health improvements across the aging population. Frailty is currently measured using aggregate scores, which obscure etiological pathways that are only relevant to subcomponents of frailty. Here we perform a multivariate genome-wide association study of the latent genetic architecture between 30 frailty deficits, which identifies 408 genomic risk loci. Our model includes a general factor of genetic overlap across all deficits, plus six new factors indexing a shared genetic signal across specific groups of deficits. We demonstrate the added clinical and etiological value of the six factors, including predicting frailty in external datasets, highlighting divergent genetic correlations with clinically relevant outcomes and uncovering unique underlying biology linked to aging. We show that nuanced models of frailty are key to understanding its causes and how it relates to worse health. |
| © 2025. The Author(s), under exclusive licence to Springer Nature America, Inc. |
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| DATE PUBLISHED |
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| HISTORY |
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| PUBSTATUS |
PUBSTATUSDATE |
| received |
2024/07/30 |
| accepted |
2025/06/18 |
| medline |
2025/08/12 06:27 |
| pubmed |
2025/08/05 00:29 |
| entrez |
2025/08/04 23:24 |
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| AUTHORS |
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| NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
| Foote IF |
|
Foote |
Isabelle F |
IF |
|
Centre for Preventive Neurology, Wolfson Institute of Population Health, Queen Mary University of London, London, UK. isabelle.foote@colorado.edu. |
| Flint JP |
|
Flint |
Jonny P |
JP |
|
Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK. |
| Fürtjes AE |
|
Fürtjes |
Anna E |
AE |
|
Department of Psychology, School of Philosophy, Psychology and Language Sciences, University of Edinburgh, Edinburgh, UK. |
| Lawrence JM |
|
Lawrence |
Jeremy M |
JM |
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Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA. |
| Mullin DS |
|
Mullin |
Donncha S |
DS |
|
Centre for Clinical Brain Sciences, Division of Psychiatry, University of Edinburgh, Edinburgh, UK. |
| Fisk JD |
|
Fisk |
John D |
JD |
|
Division of Geriatric Medicine, Dalhousie University, Halifax, Nova Scotia, Canada. |
| Karakach TK |
|
Karakach |
Tobias K |
TK |
|
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada. |
| Rutenberg A |
|
Rutenberg |
Andrew |
A |
|
Department of Physics and Atmospheric Science, Dalhousie University, Halifax, Nova Scotia, Canada. |
| Martin NG |
|
Martin |
Nicholas G |
NG |
|
Brain and Mental Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. |
| Lupton MK |
|
Lupton |
Michelle K |
MK |
|
School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia. |
| Llewellyn DJ |
|
Llewellyn |
David J |
DJ |
|
Alan Turing Institute, London, UK. |
| Ranson JM |
|
Ranson |
Janice M |
JM |
|
University of Exeter Medical School, University of Exeter, Exeter, UK. |
| Cox SR |
|
Cox |
Simon R |
SR |
|
Department of Psychology, School of Philosophy, Psychology and Language Sciences, University of Edinburgh, Edinburgh, UK. |
| Luciano M |
|
Luciano |
Michelle |
M |
|
Department of Psychology, School of Philosophy, Psychology and Language Sciences, University of Edinburgh, Edinburgh, UK. |
| Rockwood K |
|
Rockwood |
Kenneth |
K |
|
Division of Geriatric Medicine, Dalhousie University, Halifax, Nova Scotia, Canada. |
| Grotzinger AD |
|
Grotzinger |
Andrew D |
AD |
|
Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA. |
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| INVESTIGATORS |
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| JOURNAL |
|
| VOLUME: 57 |
| ISSUE: 8 |
| TITLE: Nature genetics |
| ISOABBREVIATION: Nat Genet |
| YEAR: 2025 |
| MONTH: Aug |
| DAY: |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Internet |
| ISSN: 1546-1718 |
| ISSNTYPE: Electronic |
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| MEDLINE JOURNAL |
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| MEDLINETA: Nat Genet |
| COUNTRY: United States |
| ISSNLINKING: 1061-4036 |
| NLMUNIQUEID: 9216904 |
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| PUBLICATION TYPE |
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| PUBLICATIONTYPE TEXT |
| Journal Article |
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| COMMENTS AND CORRECTIONS |
|
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| GRANTS |
|
| GRANTID |
AGENCY |
COUNTRY |
| R01AG073593 |
U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) |
|
| RF1AG073593 |
U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) |
|
| R01MH120219 |
U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) |
|
| 221890/Z/20/Z |
Wellcome Trust (Wellcome) |
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| GENERAL NOTE |
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| KEYWORDS |
|
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| MESH HEADINGS |
|
| DESCRIPTORNAME |
QUALIFIERNAME |
| Humans |
|
| Frailty |
genetics |
| Genome-Wide Association Study |
methods |
| Aged |
methods |
| Male |
methods |
| Aging |
genetics |
| Female |
genetics |
| Models, Genetic |
genetics |
| Aged, 80 and over |
genetics |
| Genomics |
methods |
| Polymorphism, Single Nucleotide |
genetics |
| Genetic Predisposition to Disease |
genetics |
| Latent Class Analysis |
genetics |
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| SUPPLEMENTARY MESH |
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| GENE SYMBOLS |
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| CHEMICALS |
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| OTHER ID's |
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