High-resolution arrays reveal burden of copy number variations on Parkinson disease genes associated with increased disease risk in random cohorts

Background: Parkinson disease (PD) is a neurological disease responsible for a considerable rate of mortality and morbidity in the society. Since the symptoms of the disease appear much later than the actual onset of neuron degeneration, a majority of cases remain undiagnosed until the manifestation of the symptoms.
Objectives: In order to investigate the existence of such susceptibility in the population, we analyzed Copy Number Variation (CNV) influences on PD genes in 1715 individuals from 12 different populations.
Results: Overall, 16 CNV-PD genes, 3 known to be causal and 13 associated, were found to be significantly enriched. PARK2, was under heavy burden with ~1% of the population containing CNV in the exonic region. The impact of these genes on the genome and disease pathway was analyzed using several genome analysis tools. Protein interaction network of CNV-PD genes revealed a complex interaction of molecules forming a major hub by the α-Synuclein, whose direct interactors, LRRK2, PARK2 and ATP13A2 are under CNV influence.
Conclusions: We hypothesize that CNVs may not be the initiating event in the pathogenesis of PD and remain latent until additional secondary hits are acquired and also propose novel genes that may fall under the PD pathway which contribute in pathogenesis.

背景：帕金森病（Parkinson disease, PD）是一种神经系统疾病，在社会中造成了可观的死亡与发病负担。由于该病的临床症状出现时间远晚于神经元变性的实际起始时间，多数病例直至症状显现才得以确诊。
目标：为探究人群中是否存在此类易感性，我们对来自12个不同人群的1715名个体展开分析，考察拷贝数变异（Copy Number Variation, CNV）对帕金森病相关基因的影响。
结果：总体而言，共发现16个与帕金森病相关的拷贝数变异基因，其中3个为已知致病基因，13个为关联基因，均呈现显著富集特征。PARK2基因承受着较重的变异负荷，约1%的人群其外显子区域存在拷贝数变异。我们借助多款基因组分析工具，对这些基因在基因组层面及疾病通路中的作用影响进行了分析。CNV相关帕金森病基因的蛋白质相互作用网络显示，分子间存在复杂的相互作用，α-突触核蛋白（α-Synuclein）构成了核心作用枢纽；其直接相互作用蛋白LRRK2、PARK2及ATP13A2均处于拷贝数变异的影响范围内。
结论：本研究提出假设，拷贝数变异或许并非帕金森病发病机制中的起始事件，而是在获得额外二次打击之前处于潜伏状态；同时我们还提出了若干可能归属于帕金森病通路、参与疾病发病过程的新候选基因。