Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 Culture West Road, Jinan, Shandong 250012, China; Healthcare Big Data Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
Department of Psychology, Zibo Maternal and Child Health Care Hospital, Zibo, Shandong 255000, China.
Psychiatry Res. 2022 Nov;317:114791. doi: 10.1016/j.psychres.2022.114791. Epub 2022 Aug 13.
Genome-wide association studies (GWAS) have identified some variants for movement-related adverse antipsychotic effects (MAAE), while how these variants confer MAAE remains unclear. We used the probabilistic Mendelian randomization (PMR) method to identify candidate proteins for MAAE by integrating MAAE GWASs and protein quantitative trait loci (pQTL) data. An independent pQTL data from the Banner project and brain-derived eQTL data were used to perform confirmatory PMR. A total of 56 proteins were identified as candidate targets for MAAE after false discovery rates (FDR) correction, such as GRIN2B, ADRA1A, and PED4B. 12 genes were replicated in the confirmatory PMR, and 18 genes had consistent evidence at the transcript level. Furthermore, we investigated the associations between candidate proteins and the motor symptoms of Parkinson's disease (PD). There were 24, 38, and 10 candidate proteins that were significantly associated with PD, PD motor subtypes, and PD motor progression, respectively. Enrichment analysis identified 34 GO terms and 17 pathways that may be involved in MAAE, such as glutamatergic synapse, glutamate receptor complex, and GABAergic synapse. Our study identified multiple candidate genes and pathways that were associated with MAAE, providing new insights into the biological mechanism of MAAE and targets for further mechanistic and therapeutic studies.
全基因组关联研究（GWAS）已经确定了一些与运动相关的抗精神病药物不良反应（MAAE）相关的变异，而这些变异如何导致 MAAE 仍不清楚。我们使用概率性孟德尔随机化（PMR）方法，通过整合 MAAE GWAS 和蛋白质数量性状基因座（pQTL）数据，来鉴定 MAAE 的候选蛋白。使用 Banner 项目的独立 pQTL 数据和大脑衍生的 eQTL 数据进行确认性 PMR。经过错误发现率（FDR）校正后，共有 56 种蛋白质被鉴定为 MAAE 的候选靶点，如 GRIN2B、ADRA1A 和 PED4B。在确认性 PMR 中，有 12 个基因得到了复制，18 个基因在转录水平上有一致的证据。此外，我们还研究了候选蛋白与帕金森病（PD）运动症状之间的关联。有 24、38 和 10 个候选蛋白分别与 PD、PD 运动亚型和 PD 运动进展显著相关。富集分析确定了 34 个 GO 术语和 17 个可能参与 MAAE 的途径，如谷氨酸能突触、谷氨酸受体复合物和 GABA 能突触。我们的研究鉴定了多个与 MAAE 相关的候选基因和途径，为 MAAE 的生物学机制和进一步的机制和治疗研究提供了新的见解。
