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

IF 3.5 2区医学 Q2 GENETICS & HEREDITY

Journal of Medical Genetics Pub Date : 2024-04-19 DOI:10.1136/jmg-2023-109295

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

{"title":"Iron and risk of dementia: Mendelian randomisation analysis in UK Biobank.","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","doi":"10.1136/jmg-2023-109295","DOIUrl":null,"url":null,"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.","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"435-442"},"PeriodicalIF":3.5000,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11041574/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medical Genetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1136/jmg-2023-109295","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}

引用次数: 0

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.

查看原文本刊更多论文

铁与痴呆症风险：英国生物库的孟德尔随机分析。

背景：脑铁沉积在痴呆症中很常见，但血清铁是否是致病风险因素尚不清楚。我们的目的是确定血清铁状态生物标志物较高的遗传易感性是否会增加痴呆症和灰质萎缩的风险：我们对英国生物库参与者进行了分析，根据与1000基因组计划的遗传相似性，将其分为欧洲组（N=451284）、非洲组（N=7477）和南亚组（N=9570）。利用孟德尔随机化方法，我们从医院和初级保健记录中估算了遗传预测血清铁（转铁蛋白饱和度 [TSAT] 和铁蛋白）、灰质体积与临床定义的痴呆（包括阿尔茨海默病 [AD]、非 AD 痴呆和血管性痴呆）遗传责任之间的关联。我们还对TSAT多基因评分对临床定义的非老年痴呆症风险进行了时间到事件（竞争风险）分析：结果：在欧洲人中，较高的遗传预测 TSAT 会增加痴呆症的遗传风险（Odds Ratio [OR]：1.15，95% 置信区间 [CI] 1.04 至 1.26，p=0.0051）、非 AD 痴呆（OR：1.27，95% CI 1.12 至 1.45，p=0.00018）和血管性痴呆（OR：1.37，95% CI 1.12 至 1.69，p=0.0023），但与 AD 无关（OR：1.00，95% CI 0.86 至 1.15，p=0.97）。在非洲裔参与者中，较高的 TSAT 也与非 AD 痴呆症风险的增加有关，但与南亚裔群体无关。在使用 TSAT 多基因评分进行的生存分析中，该效应与载脂蛋白-E ε4基因型无关（调整亚分布危险比：1.74，95% CI 1.33 至 2.28，p=0.00006）。遗传预测的TSAT与尾状核、丘脑和丘脑灰质体积较低有关，而与其他相关区域无关：讨论：遗传学证据表明，在欧洲和非洲群体中，较高的 TSAT 与临床定义的非老年痴呆症和血管性痴呆症风险之间存在因果关系。这种关联似乎与载脂蛋白-E ε4无关。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Journal of Medical Genetics 医学-遗传学

CiteScore

7.60

自引率

2.50%

发文量

审稿时长

4-8 weeks

期刊介绍： Journal of Medical Genetics is a leading international peer-reviewed journal covering original research in human genetics, including reviews of and opinion on the latest developments. Articles cover the molecular basis of human disease including germline cancer genetics, clinical manifestations of genetic disorders, applications of molecular genetics to medical practice and the systematic evaluation of such applications worldwide.