Shi Guolin, Wu Tingting, Li Xuetao, Zhao Debin, Yin Qiuyuan, Zhu Lei
Department of Neurosurgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming, Yunnan, China.
Front Neurosci. 2024 May 3;18:1385675. doi: 10.3389/fnins.2024.1385675. eCollection 2024.
MicroRNAs (miRNAs) have pivotal roles in gene regulation. Circulating miRNAs have been developed as novel candidate non-invasive biomarkers for diagnosis, prognosis, and treatment response for diseases. However, miRNAs that have causal effects on Parkinson's Disease (PD) remain largely unknown. To investigate the causal relationships between miRNAs and PD, here we conduct a Mendelian randomization (MR) study.
This study utilized the summary-level data of respective genome-wide association studies (GWAS) for 2083 miRNAs and seven PD-related outcomes to comprehensively reveal the causal associations between the circulating miRNAs and PD. Two-sample MR design was deployed and the causal effects were estimated with inverse variance weighted, MR-Egger, and weighted median. Comprehensively sensitive analyses were followed, including Cochran's test, MR-Egger intercept test, MR-PRESSO, and leave-one-out analysis, to validate the robustness of our results. Finally, we investigated the potential role of the MR significant miRNAs by predicting their target genes and functional enrichment analysis.
Inverse variance weighted estimates suggested that two miRNAs, miR-205-5p (β = -0.46, 95%CI: -0.690 to -0.229, = 9.3 × 10) and miR-6800-5p (β = -0.389, 95%CI: -0.575 to -0.202, = 4.32 × 10), significantly decreased the rate of cognitive decline among PD patients. In addition, eight miRNAs were nominally associated with more than three PD-related outcomes each. No significant heterogeneity of instrumental variables or horizontal pleiotropy was found. Gene Ontology (GO) analysis showed that the targets of these causal miRNAs were significantly enriched in cell cycle, apoptotic, and aging pathways.
This MR study identified two miRNAs whose genetically regulated expression might have a causal role in the development of PD dementia. Our findings provided potential miRNA biomarkers to make better and early diagnoses and risk assessments of PD.
微小RNA（miRNA）在基因调控中起关键作用。循环miRNA已被开发为用于疾病诊断、预后和治疗反应的新型候选非侵入性生物标志物。然而，对帕金森病（PD）具有因果效应的miRNA在很大程度上仍不为人知。为了研究miRNA与PD之间的因果关系，我们在此进行了一项孟德尔随机化（MR）研究。
本研究利用了2083个miRNA和7个PD相关结局各自的全基因组关联研究（GWAS）的汇总水平数据，以全面揭示循环miRNA与PD之间的因果关联。采用两样本MR设计，并使用逆方差加权、MR-Egger和加权中位数估计因果效应。随后进行了全面的敏感性分析，包括 Cochr an检验、MR-Egger截距检验、MR-PRESSO和留一法分析，以验证我们结果的稳健性。最后，我们通过预测其靶基因和功能富集分析来研究MR显著miRNA的潜在作用。
逆方差加权估计表明，两种miRNA，即miR-205-5p（β = -0.46，95%CI：-0.690至-0.229，P = 9.3×10）和miR-6800-5p（β = -0.389，95%CI：-0.575至-0.202，P = 4.32×10），显著降低了PD患者的认知衰退率。此外，有8种miRNA各自与超过3个PD相关结局存在名义上的关联。未发现工具变量的显著异质性或水平多效性。基因本体（GO）分析表明，这些因果miRNA的靶标在细胞周期、凋亡和衰老途径中显著富集。
这项MR研究确定了两种miRNA，其基因调控表达可能在PD痴呆的发生发展中具有因果作用。我们的研究结果提供了潜在的miRNA生物标志物，以更好地进行PD的早期诊断和风险评估。
