AbstractObservational studies have suggested the potential benefits of several medications for Parkinson’s disease (PD) and their potential for repurposing. However, the conclusions drawn from these studies are not entirely consistent. To address this inconsistency, we used the two-sample Mendelian randomization (MR) method to explore the putative causal relationships between 23 medications and the risk and progression of PD.

摘要观察性研究表明，几种药物对帕金森病（PD）的潜在益处及其重新利用的潜力。然而，从这些研究中得出的结论并不完全一致。为了解决这种不一致性，我们使用双样本孟德尔随机化（MR）方法来探索23种药物与PD风险和进展之间的假定因果关系。

We applied inverse-variance weighted meta-analysis (IVW) to combine MR estimates. Additionally, sensitivity analyses were conducted to evaluate the robustness of the results. Our genetic evidence suggests that thyroid preparations and calcium channel blockers reduce the risk of PD, and salicylic acid and derivatives slow the progression of PD motor symptoms.

我们应用逆方差加权荟萃分析（IVW）来结合MR估计。此外，还进行了敏感性分析以评估结果的稳健性。。

Additionally, genetic evidence also suggests that four medications were associated with PD risk or progression, but the sensitivity analysis revealed that three of the medications may have interference caused by reverse causality. Our findings suggest that there are weak causal relationships between several medications and the risk or progression of PD.

此外，遗传证据还表明，四种药物与PD风险或进展有关，但敏感性分析显示，其中三种药物可能具有由反向因果关系引起的干扰。我们的研究结果表明，几种药物与PD的风险或进展之间存在微弱的因果关系。

Though further replication studies are needed to verify these findings, these new insights may help in understanding the etiology of the disease, generate new clues related to drug discovery, and quantify the risk of future drug intake..

尽管需要进一步的复制研究来验证这些发现，但这些新的见解可能有助于了解疾病的病因，产生与药物发现相关的新线索，并量化未来药物摄入的风险。。

IntroductionParkinson’s disease (PD) is the second most common neurodegenerative disease, and it is characterized by the fastest growing prevalence, mortality, and disability-adjusted life expectancy in the neurological disease category1. An estimated 6.1 million individuals globally had a PD diagnosis in 2016, which is 2.4 times higher than in 19902,3.

。2016年，全球估计有610万人患有PD诊断，比19902年高2.4倍[3]。

The course of PD is considered irreversible. Its typical pathophysiology involves the death of dopaminergic neurons and the accumulation of Lewy bodies in the cytoplasm of neurons, which is mainly manifested clinically as resting tremor, bradykinesia, rigidity, and postural gait disorders4. In addition to the above typical features, some accompanying symptoms can also affect the quality of life of patients with PD and lead to faster disease progression, including mild cognitive impairment and autonomic dysfunction (such as urinary dysfunction, constipation, and blood pressure dysregulation), among others5.

PD的过程被认为是不可逆的。其典型的病理生理学涉及多巴胺能神经元的死亡和路易体在神经元细胞质中的积累，临床上主要表现为静息性震颤，运动迟缓，僵硬和姿势步态障碍4。除了上述典型特征外，一些伴随症状也会影响PD患者的生活质量，并导致疾病进展更快，包括轻度认知障碍和自主神经功能障碍（如尿功能障碍，便秘和血压失调）等5。

It is now widely believed that in addition to traditional therapies, modulation of non-dopaminergic pathways can lead to other treatment options6.Over the past two decades, there have been significant advancements in the development of new medications for the treatment of PD, with several medications aimed at improving symptoms have come to market5.

现在人们普遍认为，除了传统疗法外，非多巴胺能途径的调节还可以导致其他治疗选择6。在过去的二十年中，用于治疗PD的新药的开发取得了重大进展，几种旨在改善症状的药物已上市5。

However, to date, no drug has been discovered that can truly slow down or stop the progression of PD. This means that, due to the lack of effective disease-modifying therapies, once diagnosed, patients with PD ultimately experience unbearable disability and premature death7. Consequently, before a cure is found, neuroprotective therapies that slow or halt disease progression and prevent the accumulation of disability remain a top priority in drug development4,7.

然而，迄今为止，尚未发现任何药物可以真正减缓或阻止PD的进展。这意味着，由于缺乏有效的疾病缓解疗法，一旦确诊，PD患者最终会经历无法忍受的残疾和过早死亡7。因此，在找到治愈方法之前，减缓或阻止疾病进展并防止残疾积累的神经保护疗法仍然是药物开发的首要任务4,7。

The discove.

迪斯科舞厅。

stands for Mini-Mental State Examination, and MoCA stands for Montreal Cognitive Assessment.Full size imageFig. 3MR analysis results for thyroid preparation use and its impact on PD risk. (A) Scatter plot illustrating potential effects of SNPs on Thyroid preparation use and PD risk using IVW, MR-Egger, and weighted median methods.

代表迷你精神状态检查，MoCA代表蒙特利尔认知评估。全尺寸图像图。。（A） 散点图显示了使用IVW，MR-Egger和加权中位数方法SNP对甲状腺制剂使用和PD风险的潜在影响。

The slope of fitted lines represents the estimated MR effect per method. At the same time, the 95% confidence interval (CI) for the impact of size on thyroid preparation use and PD risk is shown as vertical and horizontal lines, respectively. (B) Funnel plot for thyroid preparation use, showing estimation using the inverse of the standard error of causal estimate with each SNP as a tool.

拟合线的斜率表示每种方法估计的MR效应。同时，大小对甲状腺制剂使用和PD风险影响的95%置信区间（CI）分别显示为垂直线和水平线。（B） 甲状腺制剂使用的漏斗图，显示使用每个SNP作为工具，使用因果估计的标准误差的倒数进行估计。

The vertical line depicts the estimated causal effect obtained using IVW and MR-Egger methods. (C) Forest plot demonstrating the impact of each SNP in the MR analysis. (D) Forest plot presenting the leave-one-out sensitivity analysis results, where each SNP in the instrument is iteratively removed to check the result’s stability.Full size imageIn addition, some medications have been found to potentially increase the risk of PD or accelerate its progression (Table 1, Supplementary Table 4–8, Supplementary Fig. 3–6).

垂直线描绘了使用IVW和MR-Egger方法获得的估计因果效应。（C） 森林图显示了MR分析中每个SNP的影响。（D） 森林图显示了留一法灵敏度分析结果，其中迭代删除仪器中的每个SNP以检查结果的稳定性。全尺寸图像此外，已经发现一些药物可能会增加PD的风险或加速其进展（表1，补充表4-8，补充图3-6）。

These medications included antidepressants (IVW: OR = 1.26; 95% CI 1.04, 1.52; P = 0.018; PD risk), diuretics (IVW: β = 0.15; 95% CI 0.01, 0.29; P = 0.040; UPDRS3), antimigraine preparations (IVW: β = 0.15; 95% CI 0.02, 0.29; P = 0.027; UPDRS3), and drugs affecting bone structure and mineralization (IVW: β = − 1.22; 95% CI − 2.25, − 0.18; P = 0.021; UPDRS3).

这些药物包括抗抑郁药（IVW:OR==1.26；95%CI 1.04,1.52；P=0.018；PD风险）、利尿剂（IVW:β==0.15；95%CI 0.01，0.29；P=0.040；UPDRS3）、抗偏头痛制剂。

The analyses in this study detected no heterogeneity, pleiotropy, or outliers for the SNPs included in the analysis using the aforementioned sensitivity testing methods. However, Steiger’s analy.

本研究中的分析使用上述敏感性测试方法未检测到分析中包含的SNP的异质性，多效性或异常值。然而，施泰格的分析。

Data availability

数据可用性

The summary statistics analyzed in the study are included in the article. Further inquiries can be directed to the corresponding author to make it accurate.

本文包含了研究中分析的汇总统计数据。进一步的询问可以直接联系通讯作者以使其准确。

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Download referencesAcknowledgementsThe authors thank all the relevant consortiums and investigators for the management and sharing of summary-level data.FundingThis work was funded by the National Natural Science Foundation of China (81060096; 81560202) and the Natural Science Foundation of Hainan (821QN0979); Hainan Key Scientific Research Projects (14A110060), Key R&D Plan Projects of Hainan Province (ZDYF2021SHFZ091), Hainan Natural Science Foundation Innovative Research Team Projects (2016CXTD010), Key Educational Reform Projects of Hainan Province (Hnjg2019ZD-15), and High-level Talents of the Hainan Natural Science Foundation (820RC759).

下载参考文献致谢作者感谢所有相关财团和调查人员管理和共享摘要级数据。资助这项工作由国家自然科学基金（81060096；81560202）和海南省自然科学基金（821QN0979）资助；。

This work was Supported by the Construction Project of Hainan Province Clinical Medical Center and Science, Innovation Platform for Academicians of Hainan Province. The funding bodies had no role in the design of the study; the collection, analysis, or interpretation of the data; or the writing of the manuscript.Author informationAuthor notesThese authors contributed equally: Qitong Wang, Fang Liu and Xinyu Wang.Authors and AffiliationsDepartment of Neurology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, 570311, Hainan, ChinaQitong Wang, Fang Liu, Xinyu Wang, Lifan Zhong, Benchi Cai & Tao ChenHainan Provincial Bureau of Disease Prevention and Control, Haikou, 570100, ChinaTao ChenAuthorsQitong WangView author publicationsYou can also search for this author in.

这项工作得到了海南省临床医学中心和海南省院士科学创新平台建设项目的支持。资助机构在研究的设计中没有任何作用；数据的收集、分析或解释；或手稿的撰写。作者信息作者注意到这些作者做出了同样的贡献：王启通，刘芳和王新宇。作者和附属机构海南医科大学海南附属医院海南总医院神经内科，海南海口，570311，中国海口，王启通，刘芳，王新宇，钟立凡，蔡本志和陈涛海南省疾病预防控制局，海口，570100，中国陈涛作者王启通观点作者出版物您也可以在中搜索作者。

PubMed Google ScholarFang LiuView author publicationsYou can also search for this author in

PubMed Google ScholarFang LiuView作者出版物您也可以在

PubMed Google ScholarXinyu WangView author publicationsYou can also search for this author in

PubMed Google ScholarXinyu WangView作者出版物您也可以在

PubMed Google ScholarLifan ZhongView author publicationsYou can also search for this author in

PubMed Google ScholarLifan ZhongView作者出版物您也可以在

PubMed Google ScholarBenchi CaiView author publicationsYou can also search for this author in

PubMed Google ScholarBenchi CaiView作者出版物您也可以在

PubMed Google ScholarTao ChenView author publicationsYou can also search for this author in

PubMed Google ScholarTao ChenView作者出版物您也可以在

PubMed Google ScholarContributionsW.Q.: Conceptualization, Writing—original draft, Formal analysis. L.F.: Writing—original draft, Formal analysis. W.X.: Writing—original draft, Formal analysis. Z.L.: Writing; review & editing-Equal. C.B.: Conceptualization, Writing—review & editing, Formal analysis.

PubMed谷歌学术贡献软件。Q、 ：概念化，撰写原稿，形式分析。五十、 。W、 X.：撰写初稿，形式分析。Z、 L.：写作；审阅和编辑相等。C、 概念化，写作评论和编辑，形式分析。

C.T.: Conceptualization, Writing—review & editing, Formal analysis. All authors reviewed the manuscript.Corresponding authorsCorrespondence to.

C、 T.：概念化，写作评论和编辑，形式分析。所有作者都审阅了手稿。通讯作者通讯。

Benchi Cai or Tao Chen.Ethics declarations

蔡本驰或陈涛。道德宣言

Competing interests

相互竞争的利益

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Reprints and permissionsAbout this articleCite this articleWang, Q., Liu, F., Wang, X. et al. Identifying potential repurposable medications for Parkinson’s disease through Mendelian randomization analysis.

转载和许可本文引用本文Wang，Q.，Liu，F.，Wang，X。等人。通过孟德尔随机化分析确定帕金森病的潜在可再利用药物。

Sci Rep 14, 19670 (2024). https://doi.org/10.1038/s41598-024-70758-zDownload citationReceived: 22 December 2023Accepted: 21 August 2024Published: 24 August 2024DOI: https://doi.org/10.1038/s41598-024-70758-zShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

Sci Rep 1419670（2024）。https://doi.org/10.1038/s41598-024-70758-zDownload引文接收日期：2023年12月22日接收日期：2024年8月21日发布日期：2024年8月24日OI：https://doi.org/10.1038/s41598-024-70758-zShare本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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KeywordsMedicationParkinson’s diseaseMendelian randomizationGenetic epidemiology

关键词适应症帕金森病孟德尔随机化遗传流行病学

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