| Title: | Iron and risk of dementia: Mendelian randomisation analysis in UK Biobank |
| Journal: | Journal of Medical Genetics |
| Published: | 8 Jan 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/38191510/ |
| DOI: | https://doi.org/10.1136/jmg-2023-109295 |
| URL: | https://jmg.bmj.com/content/jmedgenet/early/2024/01/08/jmg-2023-109295.full.pdf |
| Citations: | 1 (1 in last 2 years) as of 8 Aug 2024 |
Publication 8984
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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.</p>
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.</p>
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.</p>
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.</p>
11 Authors
- Francesco Casanova
- Qu Tian
- Janice L Atkins
- Andrew R Wood
- Daniel Williamson
- Yong Qian
- David Zweibaum
- Jun Ding
- David Melzer
- Luigi Ferrucci
- Luke C Pilling
1 Application
| Application ID | Title |
|---|---|
| 83534 | Understanding two novel factors related to motor impairment in the development of dementia - UK Biobank |
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