Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London, UK.
UCL Movement Disorders Centre, University College London, London, UK.
Mov Disord. 2021 Feb;36(2):424-433. doi: 10.1002/mds.28342. Epub 2020 Oct 28.
There are currently no treatments that stop or slow the progression of Parkinson's disease (PD). Case-control genome-wide association studies have identified variants associated with disease risk, but not progression. The objective of the current study was to identify genetic variants associated with PD progression.
We analyzed 3 large longitudinal cohorts: Tracking Parkinson's, Oxford Discovery, and the Parkinson's Progression Markers Initiative. We included clinical data for 3364 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, in which we combined multiple assessments using a principal components analysis to derive scores for composite, motor, and cognitive progression. These scores were analyzed in linear regression in genome-wide association studies. We also performed a targeted analysis of the 90 PD risk loci from the latest case-control meta-analysis.
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 composite and cognitive progression in PD. Conditional analysis revealed several independent signals in the APOE locus for cognitive progression. No single variants were associated with motor progression. However, in gene-based analysis, ATP8B2, a phospholipid transporter related to vesicle formation, was nominally associated with motor progression (P = 5.3 × 10 ).
We provide early evidence that this new method in PD improves measurement of symptom progression. We show that the APOE ε4 allele drives progressive cognitive impairment in PD. Replication of this method and results in independent cohorts are needed. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
目前尚无阻止或减缓帕金森病（PD）进展的治疗方法。病例对照全基因组关联研究已经确定了与疾病风险相关的变体，但与进展无关。本研究的目的是确定与 PD 进展相关的遗传变体。
我们分析了 3 个大型纵向队列：帕金森病追踪、牛津发现和帕金森病进展标志物倡议。我们纳入了 3364 名患者的临床数据，共 12144 个观察结果（平均随访 4.2 年）。我们使用 PD 的新方法，采用与亨廷顿病类似的方法，使用主成分分析对多次评估进行组合，得出综合、运动和认知进展的评分。这些评分在全基因组关联研究中进行线性回归分析。我们还对最新病例对照荟萃分析中的 90 个 PD 风险基因座进行了靶向分析。
与病例对照研究中 PD 风险相关的变体与 PD 发病年龄与 PD 进展之间没有重叠。APOE ε4 标记变体 rs429358 与 PD 的综合和认知进展显著相关。条件分析显示，APOE 基因座中存在几个与认知进展相关的独立信号。没有单一变体与运动进展相关。然而，在基于基因的分析中，与囊泡形成有关的磷脂转运体 ATP8B2 与运动进展呈显著相关（P = 5.3×10-5）。
我们提供了早期证据，证明 PD 的这种新方法可改善症状进展的测量。我们表明，APOE ε4 等位基因导致 PD 进行性认知障碍。需要在独立队列中复制这种方法和结果。
