Wan Ying, Rong Lu, Li Qingyuan, Liu Suzhi, Li Wentao, Ye Min, Luo Weifeng, Xie Anmu, Shao Jingsong, Guo Dengjun, Zhang Xiaoping, Zhang Kezhong, Liu Zhenguo
Department of Neurology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Shandong Province, Qingdao, China.
Mol Neurobiol. 2025 Apr 29. doi: 10.1007/s12035-025-04930-5.
Levodopa induced dyskinesia (LID) is a serious side effect of levodopa treatment in Parkinson's disease (PD), with limited interventions. Understanding the genetic impact on LID would help inform future intervention studies. We performed integrative genomic analysis approaches to identify the genetic determinants of LID in a Chinese multi-center prospective, observational PD cohort. In this cohort, 46 of 315 PD patients developed LID during 2.5 years of follow-up. First, we performed a genome-wide association study (GWAS) in this cohort, followed by a meta-analysis integrating our GWAS summary data with additional data of European ancestry. Both GWAS analyses identified the Bromodomain Containing 3 (BRD3) as a LID susceptibility gene (P < 5 × 10); however, the genetic variants within the BRD3 gene differed between the analyses. Then, we conducted a multi-tissue transcriptome-wide association study (TWAS) through integrating our GWAS summary data with six gene expression quantitative trait loci (eQTLs) datasets from tissues involved in the levodopa transport-to-function pathway, including stomach, blood, caudate, putamen, nucleus accumbens, and frontal cortex. We found that the expression levels of the TRAPPC12 Antisense RNA 1 (TRAPPC12-AS1) and Williams Beuren Syndrome Chromosome Region 27 (WBSCR27) in all tissues were associated with LID occurrence. Finally, we executed the summary data-based mendelian randomization (SMR) and identified that LID was causally associated with the two genes' expression in all tissues. In conclusion, our findings support new candidate genes for LID susceptibility, providing novel potential targets for future intervention studies.
左旋多巴诱发的异动症（LID）是帕金森病（PD）左旋多巴治疗的一种严重副作用，干预措施有限。了解基因对LID的影响将有助于为未来的干预研究提供信息。我们采用综合基因组分析方法，在中国多中心前瞻性观察性PD队列中确定LID的基因决定因素。在该队列中，315例PD患者中有46例在2.5年的随访期间出现了LID。首先，我们在该队列中进行了全基因组关联研究（GWAS），然后进行了一项荟萃分析，将我们的GWAS汇总数据与欧洲血统的其他数据相结合。两项GWAS分析均确定含溴结构域蛋白3（BRD3）为LID易感基因（P < 5 × 10）；然而，两次分析中BRD3基因内的遗传变异有所不同。然后，我们通过将我们的GWAS汇总数据与来自左旋多巴转运至功能途径所涉及组织（包括胃、血液、尾状核、壳核、伏隔核和额叶皮质）的六个基因表达定量性状位点（eQTL）数据集相结合，进行了多组织转录组全关联研究（TWAS）。我们发现，所有组织中TRAPPC12反义RNA 1（TRAPPC12-AS1）和威廉姆斯-伯伦综合征染色体区域27（WBSCR27）的表达水平与LID的发生相关。最后，我们进行了基于汇总数据的孟德尔随机化（SMR），并确定LID与所有组织中这两个基因的表达存在因果关系。总之，我们的研究结果支持了LID易感性的新候选基因，为未来的干预研究提供了新的潜在靶点。
