Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia.
University of Exeter Medical School, RILD Building, RD&E Hospital Wonford, Barrack Road, Exeter, EX2 5DW, UK.
Genome Biol. 2021 Mar 26;22(1):90. doi: 10.1186/s13059-021-02275-5.
People with neurodegenerative disorders show diverse clinical syndromes, genetic heterogeneity, and distinct brain pathological changes, but studies report overlap between these features. DNA methylation (DNAm) provides a way to explore this overlap and heterogeneity as it is determined by the combined effects of genetic variation and the environment. In this study, we aim to identify shared blood DNAm differences between controls and people with Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease.
We use a mixed-linear model method (MOMENT) that accounts for the effect of (un)known confounders, to test for the association of each DNAm site with each disorder. While only three probes are found to be genome-wide significant in each MOMENT association analysis of amyotrophic lateral sclerosis and Parkinson's disease (and none with Alzheimer's disease), a fixed-effects meta-analysis of the three disorders results in 12 genome-wide significant differentially methylated positions. Predicted immune cell-type proportions are disrupted across all neurodegenerative disorders. Protein inflammatory markers are correlated with profile sum-scores derived from disease-associated immune cell-type proportions in a healthy aging cohort. In contrast, they are not correlated with MOMENT DNAm-derived profile sum-scores, calculated using effect sizes of the 12 differentially methylated positions as weights.
We identify shared differentially methylated positions in whole blood between neurodegenerative disorders that point to shared pathogenic mechanisms. These shared differentially methylated positions may reflect causes or consequences of disease, but they are unlikely to reflect cell-type proportion differences.
患有神经退行性疾病的人表现出不同的临床综合征、遗传异质性和不同的大脑病理变化，但研究报告这些特征之间存在重叠。DNA 甲基化（DNAm）提供了一种探索这种重叠和异质性的方法，因为它是由遗传变异和环境的综合作用决定的。在这项研究中，我们旨在确定对照组和阿尔茨海默病、肌萎缩侧索硬化症和帕金森病患者之间血液 DNAm 差异的共同特征。
我们使用混合线性模型方法（MOMENT）来测试每个 DNAm 位点与每种疾病的关联，该方法考虑了（未）知混杂因素的影响。虽然在肌萎缩侧索硬化症和帕金森病的每一次 MOMENT 关联分析中只有三个探针被发现具有全基因组意义（而在阿尔茨海默病中则没有），但对这三种疾病的固定效应荟萃分析则导致 12 个全基因组意义上的差异甲基化位置。在所有神经退行性疾病中，预测的免疫细胞类型比例都被打乱了。在健康衰老队列中，蛋白质炎症标志物与与疾病相关的免疫细胞类型比例衍生的特征总和评分相关，但与使用 12 个差异甲基化位置的效应大小作为权重计算的 MOMENT DNAm 衍生特征总和评分不相关。
我们在神经退行性疾病的全血中发现了共同的差异甲基化位置，这些位置指向了共同的发病机制。这些共同的差异甲基化位置可能反映了疾病的原因或后果，但它们不太可能反映细胞类型比例的差异。
