背景:在神经退行性疾病中观察到铁过载,特别是阿尔茨海默病(AD)和帕金森病(PD)。导致HFEp.C282Y变异的铁超负荷(血色素沉着症)的纯合子患痴呆和PD的风险增加。在一般人群中,脑铁沉积是神经退行性过程的原因还是继发原因尚不清楚。
方法:我们分析了39,533名欧洲遗传祖先的英国生物银行参与者的大脑MRI数据。我们研究了通过R2*和定量磁化率图(QSM)估算的8个皮质下区域的脑铁:伏隔,杏仁核,尾状,海马体,苍白球,壳核,黑质,还有丘脑.我们进行了全基因组关联研究(GWAS),并使用孟德尔随机化(MR)方法来估计脑铁对灰质体积的因果效应,和AD的风险,非AD和PD。我们还使用MR测试AD或PD的遗传倾向是否会导致脑铁增加(R2*和QSM)。
结果:在R2*和QSM的GWAS中,我们复制了83%先前报道的遗传基因座,并在所有八个大脑区域中鉴定了174个进一步的基因座。基因预测的脑铁含量较高,同时使用R2*和QSM,与尾状中较低的灰质体积有关,壳核和丘脑(例如,β-putamenQSM:-0.37,p=2*10-46)。较高的遗传预测丘脑R2*与非AD痴呆的风险增加相关(OR1.36(1.16;1.60),p=2*10-4)但不是AD(p>0.05)。在男性中,遗传预测的壳核R2*增加非AD痴呆风险,但不是女性。基因预测尾状中的铁含量较高,壳核,黑质与PD的风险增加相关(比值比QSM~黑质1.21(1.07;1.37),p=0.003)。AD或PD的遗传倾向与痴呆或PD相关区域的R2*或QSM无关。
结论:我们的遗传分析支持帕金森病的特定皮质下脑区域中铁沉积增加的因果效应,灰质体积,和非老年痴呆症。
BACKGROUND: Iron overload is observed in neurodegenerative diseases, especially Alzheimer\'s disease (AD) and Parkinson\'s disease (PD). Homozygotes for the iron-overload (haemochromatosis) causing HFE p.C282Y variant have increased risk of dementia and PD. Whether brain iron deposition is causal or secondary to the neurodegenerative processes in the general population is unclear.
METHODS: We analysed 39,533 UK Biobank participants of European genetic ancestry with brain MRI data. We studied brain iron estimated by R2* and quantitative susceptibility mapping (QSM) in 8 subcortical regions: accumbens, amygdala, caudate, hippocampus, pallidum, putamen, substantia nigra, and thalamus. We performed genome-wide associations studies (GWAS) and used Mendelian Randomization (MR) methods to estimate the causal effect of brain iron on grey matter volume, and risk of AD, non-AD and PD. We also used MR to test whether genetic liability to AD or PD causally increased brain iron (R2* and QSM).
RESULTS: In GWAS of R2* and QSM we replicated 83% of previously reported genetic loci and identified 174 further loci across all eight brain regions. Higher genetically predicted brain iron, using both R2* and QSM, was associated with lower grey matter volumes in the caudate, putamen and thalamus (e.g., Beta-putamenQSM: -0.37, p = 2*10-46). Higher genetically predicted thalamus R2* was associated with increased risk of non-AD dementia (OR 1.36(1.16;1.60), p = 2*10-4) but not AD (p > 0.05). In males, genetically predicted putamen R2* increased non-AD dementia risk, but not in females. Higher genetically predicted iron in the caudate, putamen, and substantia nigra was associated with an increased risk of PD (Odds Ratio QSM ∼ substantia-nigra 1.21(1.07;1.37), p = 0.003). Genetic liability to AD or PD was not associated with R2* or QSM in the dementia or PD-associated regions.
CONCLUSIONS: Our genetic analysis supports a causal effect of higher iron deposition in specific subcortical brain regions for Parkinson\'s disease, grey matter volume, and non-Alzheimer\'s dementia.