Long-term treatment of Parkinson's disease (PD) by levodopa leads to motor complication "wearing-off". Zonisamide is a nondopaminergic antiparkinsonian drug that can improve "wearing-off" although response to the treatment varies between individuals. To clarify the genetic basis of zonisamide responsiveness, we conducted a genome-wide association study (GWAS) on 200 PD patients from a placebo-controlled clinical trial, including 67 responders whose "off" time decreased ≥1.5 h after 12 weeks of zonisamide treatment and 133 poor responders. We genotyped and evaluated the association between 611,492 single nucleotide polymorphisms (SNPs) and "off" time reduction. We also performed whole-genome imputation, gene- and pathway-based analyses of GWAS data. For promising SNPs, we examined single-tissue expression quantitative trait loci (eQTL) data in the GTEx database. SNP rs16854023 (Mouse double minute 4, MDM4) showed genome-wide significant association with reduced "off" time (PAdjusted = 4.85 × 10-9). Carriers of responsive genotype showed >7-fold decrease in mean "off" time compared to noncarriers (1.42 h vs 0.19 h; P = 2.71 × 10-7). In silico eQTL data indicated that zonisamide sensitivity is associated with higher MDM4 expression. Among the 37 pathways significantly influencing "off" time, calcium and glutamate signaling have also been associated with anti-epileptic effect of zonisamide. MDM4 encodes a negative regulator of p53. The association between improved motor fluctuation and MDM4 upregulation implies that p53 inhibition may prevent dopaminergic neuron loss and consequent motor symptoms. This is the first genome-wide pharmacogenetics study on antiparkinsonian drug. The findings provide a basis for improved management of "wearing-off" in PD by genotype-guided zonisamide treatment.

中文翻译：

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全基因组关联研究确定了帕金森氏病患者的zonisamide反应基因。

左旋多巴对帕金森氏病（PD）的长期治疗会导致运动并发症“消退”。唑尼沙胺是一种非多巴胺能抗帕金森病药物，尽管对治疗的反应因人而异，但可以改善“衰老”。为了阐明唑尼沙胺应答性的遗传基础，我们对安慰剂对照临床试验中的200名PD患者进行了全基因组关联研究（GWAS），包括67名应答者，唑尼沙胺治疗12周后“关闭”时间减少了≥1.5小时和133位贫困者。我们进行了基因分型并评估了611,492个单核苷酸多态性（SNP）与“关闭”时间减少之间的关联。我们还对GWAS数据进行了全基因组估算，基于基因和途径的分析。对于有前途的SNP，我们检查了GTEx数据库中的单组织表达定量性状基因座（eQTL）数据。SNP rs16854023（鼠标双击，第4分钟，MDM4）显示出全基因组显着关联，且“关闭”时间减少（PA调整后= 4.85×10-9）。响应型基因携带者的平均“关闭”时间比非携带者减少了7倍（1.42小时vs.0.19小时； P = 2.71×10-7）。在计算机上，eQTL数据表明zonisamide敏感性与更高的MDM4表达有关。在显着影响“关闭”时间的37条途径中，钙和谷氨酸信号传导也与唑尼沙胺的抗癫痫作用有关。MDM4编码p53的负调节子。改善的运动波动与MDM4上调之间的关联意味着p53抑制可预防多巴胺能神经元丢失和随之而来的运动症状。这是有关抗帕金森病药物的第一个全基因组药物遗传学研究。这些发现为通过基因型引导的唑尼沙胺治疗改善PD中的“衰老”提供了依据。