Mitochondria-Related Genome-Wide Mendelian Randomization Identifies Putatively Causal Genes for Neurodegenerative Diseases.

IF 7.4 1区医学 Q1 CLINICAL NEUROLOGY

Movement Disorders Pub Date : 2025-01-22 DOI:10.1002/mds.30123

Zheyi Wang, Yize Sun, Zetai Bai, Mei Li, Deyuan Kong, Guanzhao Wu

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引用次数: 0

Abstract

Background: Mitochondrial dysfunction is increasingly recognized as a key factor in neurodegenerative diseases (NDDs), underscoring the therapeutic potential of targeting mitochondria-related genes. This study aimed to identify novel biomarkers and drug targets for these diseases through a comprehensive analysis that integrated genome-wide Mendelian randomization (MR) with genes associated with mitochondrial function.

Methods: Using existing publicly available genome-wide association studies (GWAS) summary statistics and comprehensive data on 1136 mitochondria-related genes, we initially identified a subset of genes related to mitochondrial function that exhibited significant associations with NDDs. We then conducted colocalization and summary-data-based Mendelian randomization (SMR) analyses using expression quantitative trait loci (eQTL) to validate the causal role of these candidate genes. Additionally, we assessed the druggability of the encoded proteins to prioritize potential therapeutic targets for further exploration.

Results: Genetically predicted levels of 10 genes were found to be significantly associated with the risk of NDDs. Elevated DMPK and LACTB2 levels were associated with increased Alzheimer's disease risk. Higher expression of NDUFAF2, BCKDK, and MALSU1, along with lower TTC19, raised Parkinson's disease risk. Higher ACLY levels were associated with both amyotrophic lateral sclerosis and multiple sclerosis (MS) risks, while decreased MCL1, TOP3A, and VWA8 levels raised MS risk. These genes primarily impact mitochondrial function and energy metabolism. Notably, several druggable protein targets identified are being explored for potential NDDs treatment.

Conclusions: This data-driven MR study demonstrated the causal role of mitochondrial dysfunction in NDDs. Additionally, this study identified candidate genes that could serve as potential pharmacological targets for the prevention and treatment of NDDs. © 2025 International Parkinson and Movement Disorder Society.

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线粒体相关全基因组孟德尔随机化鉴定神经退行性疾病的推定致病基因

背景：线粒体功能障碍越来越被认为是神经退行性疾病（ndd）的关键因素，强调了靶向线粒体相关基因的治疗潜力。本研究旨在通过整合全基因组孟德尔随机化（MR）与线粒体功能相关基因的综合分析，确定这些疾病的新生物标志物和药物靶点。方法：利用现有的公开全基因组关联研究（GWAS）对1136个线粒体相关基因的汇总统计和综合数据，我们初步确定了一个与线粒体功能相关的基因子集，这些基因与ndd有显著关联。然后，我们使用表达数量性状位点（eQTL）进行共定位和基于汇总数据的孟德尔随机化（SMR）分析，以验证这些候选基因的因果作用。此外，我们评估了编码蛋白的可药物性，以优先考虑潜在的治疗靶点，以进一步探索。结果：发现10个基因的遗传预测水平与ndd的风险显著相关。DMPK和LACTB2水平升高与阿尔茨海默病风险增加有关。NDUFAF2、BCKDK和MALSU1的高表达以及TTC19的低表达增加了帕金森病的风险。较高的ACLY水平与肌萎缩性侧索硬化症和多发性硬化症（MS）风险相关，而降低的MCL1、TOP3A和VWA8水平会增加MS风险。这些基因主要影响线粒体功能和能量代谢。值得注意的是，一些已确定的可药物蛋白靶点正在被探索用于潜在的ndd治疗。结论：这项数据驱动的MR研究证明了线粒体功能障碍在ndd中的因果作用。此外，本研究还确定了可能作为预防和治疗ndd的潜在药理靶点的候选基因。©2025国际帕金森和运动障碍学会。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Movement Disorders 医学-临床神经学

CiteScore

13.30

自引率

8.10%

发文量

371

审稿时长

12 months

期刊介绍： Movement Disorders publishes a variety of content types including Reviews, Viewpoints, Full Length Articles, Historical Reports, Brief Reports, and Letters. The journal considers original manuscripts on topics related to the diagnosis, therapeutics, pharmacology, biochemistry, physiology, etiology, genetics, and epidemiology of movement disorders. Appropriate topics include Parkinsonism, Chorea, Tremors, Dystonia, Myoclonus, Tics, Tardive Dyskinesia, Spasticity, and Ataxia.