Background: There are currently no treatments that stop or slow the progression of Parkinson's disease (PD). Case-control genome-wide association studies (GWASs) have identified variants associated with disease risk, but not progression. Objective: To identify genetic variants associated with PD progression in GWASs. Methods: We analysed three large, longitudinal cohorts: Tracking Parkinson's, Oxford Discovery, and the Parkinson's Progression Markers Initiative. We included clinical data for 3,364 patients with 12,144 observations (mean follow-up 4.2 years). We used a new method in PD, following a similar approach in Huntington's disease, where we combined multiple assessments using a principal components analysis to derive scores for composite, motor, and cognitive progression. These scores were analysed in linear regressions in GWASs. We also performed a targeted analysis of the 90 PD risk loci from the latest case-control meta-analysis. Results: There was no overlap between variants associated with PD risk, from case-control studies, and PD age at onset versus PD progression. The APOE ϵ4 tagging variant, rs429358, was significantly associated with the rate of composite and cognitive progression in PD. No single variants were associated with motor progression. However in gene-based analysis, variation across ATP8B2, a phospholipid transporter related to vesicle formation, was nominally associated with motor progression (p=5.3 x 10^-6). Conclusions: This new method in PD improves measurement of symptom progression. We provide strong evidence that the APOE ϵ4 allele drives progressive cognitive impairment in PD. We have also reported loci of interest which need to be tested in further studies.

中文翻译：

---

帕金森氏病认知和运动进展的全基因组关联研究

背景：目前尚无任何能阻止或减慢帕金森氏病（PD）进展的治疗方法。病例对照全基因组关联研究（GWAS）已确定与疾病风险相关但与进展无关的变异。目的：确定与GWAS中PD进展相关的遗传变异。方法：我们分析了三个纵向的大型队列：跟踪帕金森氏症，牛津发现号和帕金森氏病进展标记倡议。我们纳入了3,364例患者的临床数据，并进行了12144次观察（平均随访4.2年）。在亨廷顿舞蹈病中，我们采用了一种类似的方法，在PD中使用了一种新方法，在该方法中，我们使用主成分分析对多种评估进行了组合，以得出综合，运动和认知进展的评分。这些分数在GWAS中进行线性回归分析。我们还根据最新的病例对照荟萃分析对90个PD风险基因座进行了针对性分析。结果：病例对照研究显示，与PD风险相关的变异体与PD发病年龄和PD进展之间没有重叠。APOE ϵ4标记变体rs429358与PD的复合和认知进展速度显着相关。没有单一的变体与运动进程有关。然而，在基于基因的分析中，跨ATP8B2（与小泡形成有关的磷脂转运蛋白）的变异名义上与运动进程有关（p = 5.3 x 10 ^ -6）。结论：这种用于PD的新方法改善了症状进展的测量。我们提供有力的证据表明，APOEϵ4等位基因可驱动PD的进行性认知障碍。