Abstract Background: Biallelic PRKN mutation carriers with Parkinson's disease (PD) typically have an earlier disease onset, slow disease progression and, often, different neuropathology compared to sporadic PD patients. However, the role of heterozygous PRKN variants in the risk of PD is controversial. Objectives: We aimed to examine the association between heterozygous PRKN variants, including single nucleotide variants and copy-number variations, and PD. Methods: We fully sequenced PRKN in 2,809 PD patients and 3,629 healthy controls, including 1,965 late onset (63.97±7.79 years, 63% men) and 553 early onset PD patients (43.33±6.59 years, 68% men). PRKN was sequenced using targeted next-generation sequencing with molecular inversion probes. Copy-number variations were identified using a combination of multiplex ligation-dependent probe amplification and ExomeDepth. To examine whether rare heterozygous single nucleotide variants and copy-number variations in PRKN are associated with PD risk and onset, we used optimized sequence kernel association tests and regression models. Results: We did not find any associations between all types of PRKN variants and risk of PD. Pathogenic and likely-pathogenic heterozygous single nucleotide variants and copy-number variations were less common among PD patients (1.52%) than among controls (1.8%, false discovery rate-corrected p=0.55). No associations with age at onset and in stratified analyses were found. Conclusions: Heterozygous single nucleotide variants and copy-number variations in PRKN are not associated with Parkinson's disease. Molecular inversion probes allow for rapid and cost-effective detection of all types of PRKN variants, which may be useful for pre-trial screening and for clinical and basic science studies specifically targeting PRKN patients.

中文翻译：

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帕金森氏病的杂合PRKN变异和拷贝数变异分析

摘要 背景：与散发性PD患者相比，患有帕金森氏病（PD）的双等位PRKN突变携带者通常具有较早的疾病发作，缓慢的疾病进展以及通常不同的神经病理学。然而，杂合PRKN变体在PD风险中的作用是有争议的。 目的：我们旨在检查杂合PRKN变体（包括单核苷酸变体和拷贝数变异）与PD之间的关联。 方法：我们完全测序PRKN在2809名PD患者和3,629名健康对照，其中包括1,965晚期发作（63.97±7.79年，63名％为男性）和553名早发PD患者（43.33±6.59年，68％为男性）。PRKN使用具有分子倒置探针的靶向下一代测序技术进行测序。使用多重连接依赖探针扩增和ExomeDepth的组合来鉴定拷贝数变异。为了检查PRKN中罕见的杂合单核苷酸变异和拷贝数变异是否与PD风险和发作相关，我们使用了优化的序列核关联测试和回归模型。 结果：我们没有发现所有类型的PRKN变异与PD风险之间有任何关联。PD患者（1.52％）的致病性和可能致病性的杂合单核苷酸变异和拷贝数变异不如对照组（1.8％，错误发现率校正的p）少= 0.55）。在发病和分层分析中均未发现与年龄相关。结论：PRKN的杂合单核苷酸变异和拷贝数变异与帕金森氏病无关。分子倒置探针可快速且经济高效地检测所有类型的PRKN变异体，这可能对预审筛查以及专门针对PRKN患者的临床和基础科学研究有用。