The loss of dopaminergic neurons in the substantia nigra and the abnormal accumulation of synuclein proteins and neurotransmitters in Lewy bodies constitute the primary symptoms of Parkinson’s disease (PD). Besides environmental factors, scholars are in the early stages of comprehending the genetic factors involved in the pathogenic mechanism of PD. Although genome-wide association studies (GWAS) have unveiled numerous genetic variants associated with PD, precisely pinpointing the causal variants remains challenging due to strong linkage disequilibrium (LD) among them. Addressing this issue, expression quantitative trait locus (eQTL) cohorts were employed in a transcriptome-wide association study (TWAS) to infer the genetic correlation between gene expression and a particular trait. Utilizing the TWAS theory alongside the enhanced Joint-Tissue Imputation (JTI) technique and Mendelian Randomization (MR) framework (MR-JTI), we identified a total of 159 PD-associated genes by amalgamating LD score, GTEx eQTL data, and GWAS summary statistic data from a substantial cohort. Subsequently, Fisher’s exact test was conducted on these PD-associated genes using 5,152 differentially expressed genes sourced from 12 PD-related datasets. Ultimately, 29 highly credible PD-associated genes, including CTX1B, SCNA, and ARSA, were uncovered. Furthermore, GO and KEGG enrichment analyses indicated that these genes primarily function in tissue synthesis, regulation of neuron projection development, vesicle organization and transportation, and lysosomal impact. The potential PD-associated genes identified in this study not only offer fresh insights into the disease’s pathophysiology but also suggest potential biomarkers for early disease detection.

中文翻译：

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关节组织综合分析识别帕金森病的高危基因

黑质中多巴胺能神经元的丧失以及路易体中突触核蛋白和神经递质的异常积累构成了帕金森病（PD）的主要症状。除了环境因素外，学者们对帕金森病发病机制中涉及的遗传因素的认识还处于早期阶段。尽管全基因组关联研究（GWAS）已经揭示了许多与帕金森病相关的遗传变异，但由于它们之间存在很强的连锁不平衡（LD），精确定位因果变异仍然具有挑战性。为了解决这个问题，在全转录组关联研究（TWAS）中采用了表达数量性状基因座（eQTL）队列来推断基因表达与特定性状之间的遗传相关性。利用 TWAS 理论以及增强的关节组织插补 (JTI) 技术和孟德尔随机化 (MR) 框架 (MR-JTI)，我们通过合并 LD 评分、GTEx eQTL 数据和 GWAS 摘要，总共鉴定了 159 个 PD 相关基因来自大量群体的统计数据。随后，使用来自 12 个 PD 相关数据集的 5,152 个差异表达基因对这些 PD 相关基因进行了 Fisher 精确检验。最终，发现了 29 个高度可信的 PD 相关基因，包括 CTX1B、SCNA 和 ARSA。此外，GO和KEGG富集分析表明这些基因主要在组织合成、神经元投射发育调节、囊泡组织和运输以及溶酶体影响中发挥作用。本研究中发现的潜在帕金森病相关基因不仅为该疾病的病理生理学提供了新的见解，而且还为早期疾病检测提供了潜在的生物标志物。