Iron and risk of dementia: Mendelian randomisation analysis in UK Biobank
dc.contributor.author | Casanova, F | |
dc.contributor.author | Tian, Q | |
dc.contributor.author | Atkins, JL | |
dc.contributor.author | Wood, AR | |
dc.contributor.author | Williamson, D | |
dc.contributor.author | Qian, Y | |
dc.contributor.author | Zweibaum, D | |
dc.contributor.author | Ding, J | |
dc.contributor.author | Melzer, D | |
dc.contributor.author | Ferrucci, L | |
dc.contributor.author | Pilling, LC | |
dc.date.accessioned | 2024-01-11T13:16:11Z | |
dc.date.issued | 2024-01-08 | |
dc.date.updated | 2024-01-11T11:15:20Z | |
dc.description.abstract | Background Brain iron deposition is common in dementia, but whether serum iron is a causal risk factor is unknown. We aimed to determine whether genetic predisposition to higher serum iron status biomarkers increased risk of dementia and atrophy of grey matter. Methods We analysed UK Biobank participants clustered into European (N=451284), African (N=7477) and South Asian (N=9570) groups by genetic similarity to the 1000 genomes project. Using Mendelian randomisation methods, we estimated the association between genetically predicted serum iron (transferrin saturation [TSAT] and ferritin), grey matter volume and genetic liability to clinically defined dementia (including Alzheimer’s disease [AD], non-AD dementia, and vascular dementia) from hospital and primary care records. We also performed time-to-event (competing risks) analysis of the TSAT polygenic score on risk of clinically defined non-AD dementia. Results In Europeans, higher genetically predicted TSAT increased genetic liability to dementia (Odds Ratio [OR]: 1.15, 95% Confidence Intervals [CI] 1.04 to 1.26, p=0.0051), non-AD dementia (OR: 1.27, 95% CI 1.12 to 1.45, p=0.00018) and vascular dementia (OR: 1.37, 95% CI 1.12 to 1.69, p=0.0023), but not AD (OR: 1.00, 95% CI 0.86 to 1.15, p=0.97). Higher TSAT was also associated with increased risk of non-AD dementia in participants of African, but not South Asian groups. In survival analysis using a TSAT polygenic score, the effect was independent of apolipoprotein-E ε4 genotype (with adjustment subdistribution Hazard Ratio: 1.74, 95% CI 1.33 to 2.28, p=0.00006). Genetically predicted TSAT was associated with lower grey matter volume in caudate, putamen and thalamus, and not in other areas of interest. Discussion Genetic evidence supports a causal relationship between higher TSAT and risk of clinically defined non-AD and vascular dementia, in European and African groups. This association appears to be independent of apolipoprotein-E ε4. | en_GB |
dc.description.sponsorship | National Institute for Health and Care Research (NIHR) | en_GB |
dc.identifier.citation | Published online 8 January 2024 | en_GB |
dc.identifier.doi | https://doi.org/10.1136/jmg-2023-109295 | |
dc.identifier.uri | http://hdl.handle.net/10871/134995 | |
dc.identifier | ORCID: 0000-0003-0275-4765 (Casanova, Francesco) | |
dc.identifier | ScopusID: 18436139700 | 56592223400 (Casanova, Francesco) | |
dc.identifier | ORCID: 0000-0002-3332-8454 (Pilling, Luke C) | |
dc.language.iso | en | en_GB |
dc.publisher | BMJ Publishing Group | en_GB |
dc.rights | © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/. | en_GB |
dc.title | Iron and risk of dementia: Mendelian randomisation analysis in UK Biobank | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2024-01-11T13:16:11Z | |
dc.identifier.issn | 0022-2593 | |
dc.description | This is the final version. Available on open access from BMJ Publishing Group via the DOI in this record | en_GB |
dc.description | Data availability statement: Results are available in a public, open access repository. Access to UK Biobank participant level data requires application. UKB data are available to any bone fide researcher following application (https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access). Summary statistics for these GWAS are available to download from FigShare (DOI 10.6084/m9.figshare.21828498). | en_GB |
dc.identifier.eissn | 1468-6244 | |
dc.identifier.journal | Journal of Medical Genetics | en_GB |
dc.relation.ispartof | Journal of Medical Genetics | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | en_GB |
dcterms.dateAccepted | 2023-11-28 | |
rioxxterms.version | VoR | en_GB |
rioxxterms.licenseref.startdate | 2024-01-08 | |
rioxxterms.type | Journal Article/Review | en_GB |
refterms.dateFCD | 2024-01-11T13:14:27Z | |
refterms.versionFCD | VoR | |
refterms.dateFOA | 2024-01-11T13:16:12Z | |
refterms.panel | A | en_GB |
refterms.dateFirstOnline | 2024-01-08 |
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Except where otherwise noted, this item's licence is described as © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.
This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.