Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Via Luigi Galvani 31, 39100, Bozen/Bolzano, Italy.
Section of Neurosciences, Department G.F. Ingrassia, University of Catania, Catania, Italy.
Sci Rep. 2021 Oct 1;11(1):19582. doi: 10.1038/s41598-021-99393-8.
Levodopa is the standard long-term dopamine replacement therapy to treat Parkinson's disease (PD) symptoms. With time, levodopa may induce debilitating dyskinesias (LID), the treatment of which represents a large clinically unmet need. However, time-to-LID onset varies between patients, reflecting a possible genetic component. We performed an hypothesis-free whole-exome sequencing (WES)-based screening of time-to-LID onset and attempted replication of previously published candidate gene studies. A WES association analysis was carried out in 134 PD patients in a meta-analytical framework. Replication was attempted in an independent study of 97 PD patients. Variants from previously reported candidate genes (OPRM1, COMT, BDNF) were also specifically examined. We significantly replicated, for the first time, an association of variant rs1799971 in the OPRM1 gene with time-to-LID onset. Furthermore, we identified two novel potentially functional variants, in the MAD2L2 (rs2233019) and MAP7 (rs35350783) genes, which were significantly associated at the discovery stage. In the replication study, the two variants showed direction-consistent effects but did not achieve the replication significance threshold. Our study provides the first WES results for time-to-LID onset, where we replicate association at OPRM1, and suggest new variants in MAD2L2 and MAP7 genes that are significant in discovery, but require larger datasets for replication. The results are being made publicly available to allow for independent external validation.
左旋多巴是治疗帕金森病（PD）症状的标准长期多巴胺替代疗法。随着时间的推移，左旋多巴可能会引起使人衰弱的运动障碍（LID），而治疗这种运动障碍是目前临床上尚未满足的巨大需求。然而，LID 的发病时间在患者之间存在差异，这反映了可能存在遗传因素。我们进行了一项无假设的全外显子组测序（WES）基础上的 LID 发病时间的筛查，并尝试复制先前发表的候选基因研究。在一个荟萃分析框架中，对 134 名 PD 患者进行了 WES 关联分析。在一项独立的 97 名 PD 患者研究中，尝试了复制。还专门检查了先前报道的候选基因（OPRM1、COMT、BDNF）中的变体。我们首次显著复制了 OPRM1 基因中的变体 rs1799971 与 LID 发病时间之间的关联。此外，我们还鉴定了两个新的潜在功能变体，即 MAD2L2（rs2233019）和 MAP7（rs35350783）基因中的变体，在发现阶段这些变体具有显著相关性。在复制研究中，这两个变体表现出一致的效果，但未达到复制的显著性阈值。我们的研究提供了 LID 发病时间的首个 WES 结果，其中我们复制了 OPRM1 中的关联，并提出了 MAD2L2 和 MAP7 基因中的新变体，这些变体在发现阶段具有显著性，但需要更大的数据集进行复制。结果将公开发布，以允许独立的外部验证。
