Iron and risk of dementia: Mendelian randomisation analysis in UK Biobank

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.

Keywords: Dementia; Genetics, Population.

Figure 1

Genetically predicted transferrin saturation (TSAT) associations with dementia diagnosis in the UK Biobank (UKB) EUR-like group. Results are from Mendelian randomisation (inverse-variance weighted) analysis. Twenty TSAT genetic variants are from Moksnes et al, with outcome associations from analysis in the UKB EUR-like group. Estimates are expressed as the OR per SD in genetically predicted TSAT (95% CIs). See online supplemental table 5 and 9 for detailed results, including sensitivity analyses. AD, Alzheimer’s disease; EUR-like, European Ancestry superpopulation.

Figure 2

Cumulative risk of non-Alzheimer’s dementia, stratified by quantile of transferrin saturation polygenic score. Panel A shows the top 1% of polygenic score compared to the bottom 1% and Panel B shows the top 5% of polygenic score compared to the bottom 5%. Analysis in UK Biobank participants, adjusted for the competing risk of mortality. Shaded areas are the 95% CIs. X-axis restricted to 82 years, as very few participants attained age >82 years during follow-up. PGS, polygenic score for transferrin saturation.

Figure 3

Genetically predicted transferrin saturation (TSAT) associations with grey matter volumes in the UK Biobank EUR-like group. Results are from Mendelian randomisation (inverse-variance weighted) analysis. Twenty TSAT genetic variants are from Moksnes et al, with outcome associations from analysis in the UK Biobank EUR-like group. Estimates are expressed as unit change per SD in genetically predicted TSAT (95% CI). See online supplemental table 6 for detailed results, including sensitivity analyses. EUR-like, European Ancestry superpopulation. * = statistically significant after multiple testing correction (17 tests. p < 0.003).