Epigenome-wide association study, meta-analysis, and multiscore profiling of whole blood in Parkinson's disease

IF 3.9 2区医学 Q1 CLINICAL NEUROLOGY Annals of Clinical and Translational Neurology Pub Date : 2025-02-05 DOI:10.1002/acn3.52292

Ingeborg Haugesag Lie, Manuela M. X. Tan, Maren Stolp Andersen, Mathias Toft, Lasse Pihlstrøm

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Abstract

Objectives

An increasing body of evidence indicates altered DNA methylation in Parkinson's disease, yet the reproducibility and utility of such methylation changes are largely unexplored. We aimed to further elucidate the role of dysregulated DNA methylation in Parkinson's disease and to evaluate the biomarker potential of methylation-based profiling.

Methods

We conducted an epigenome-wide association study (EWAS) in whole blood, including 280 Parkinson's disease and 279 control participants from Oslo, Norway. Next, we took advantage of data from the Parkinson's Progression Markers Initiative (PPMI) and a previously published EWAS to conduct a whole blood EWAS meta-analysis in Parkinson's disease, incorporating results from a total of 3068 participants. Finally, we generated multiple methylation-based scores for each Oslo and PPMI participant and tested their association with disease status, individually and in a joint multiscore model.

Results

In EWAS meta-analysis, we confirm SLC7A11 hypermethylation and nominate a novel differentially methylated CpG near LPIN1. A joint multiscore model incorporating polygenic risk and methylation-based estimates of epigenetic Parkinson's disease risk, smoking, and leukocyte proportions differentiated patients from control participants with an area under the receiver-operator curve of 0.82 in the Oslo cohort and 0.65 in PPMI.

Interpretation

Our results highlight the power of DNA methylation profiling to capture multiple aspects of disease risk, indicating a biomarker potential for precision medicine in neurodegenerative disorders. The reproducibility of specific differentially methylated CpGs across data sets was limited but may improve if future studies are designed to account for disease stage and incorporate environmental exposure data.

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帕金森病全血的全基因组关联研究、荟萃分析和多重评分分析。

目的：越来越多的证据表明，DNA甲基化在帕金森病中发生了改变，但这种甲基化变化的可重复性和实用性在很大程度上尚未得到探索。我们的目的是进一步阐明DNA甲基化失调在帕金森病中的作用，并评估甲基化分析的生物标志物潜力。方法：我们在全血中进行了一项全基因组关联研究（EWAS），包括来自挪威奥斯陆的280名帕金森病患者和279名对照受试者。接下来，我们利用帕金森进展标志物倡议（PPMI）和先前发表的EWAS的数据，对帕金森病进行了全血EWAS荟萃分析，纳入了总共3068名参与者的结果。最后，我们为每个Oslo和PPMI参与者生成了多个基于甲基化的评分，并在单独和联合多重评分模型中测试了它们与疾病状态的关联。结果：在EWAS荟萃分析中，我们证实了SLC7A11的高甲基化，并在LPIN1附近发现了一个新的差异甲基化CpG。结合多基因风险和基于表观遗传帕金森病风险、吸烟和白细胞比例的甲基化估计的联合多重评分模型将患者与对照参与者区分开来，奥斯陆队列的接受者-操作者曲线下面积为0.82，PPMI的接受者-操作者曲线下面积为0.65。解释：我们的研究结果强调了DNA甲基化分析在捕捉疾病风险的多个方面的力量，表明了神经退行性疾病精准医学的生物标志物潜力。跨数据集的特异性差异甲基化CpGs的可重复性有限，但如果未来的研究旨在考虑疾病阶段并纳入环境暴露数据，则可能会得到改善。

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来源期刊

Annals of Clinical and Translational Neurology Medicine-Neurology (clinical)

CiteScore

9.10

自引率

1.90%

发文量

218

审稿时长

8 weeks

期刊介绍： Annals of Clinical and Translational Neurology is a peer-reviewed journal for rapid dissemination of high-quality research related to all areas of neurology. The journal publishes original research and scholarly reviews focused on the mechanisms and treatments of diseases of the nervous system; high-impact topics in neurologic education; and other topics of interest to the clinical neuroscience community.