LCSB, University of Luxembourg, Belvaux, Luxembourg.
Department of Life Sciences and Medicine (DLSM), University of Luxembourg, Belvaux, Luxembourg.
J Neural Transm (Vienna). 2020 May;127(5):729-748. doi: 10.1007/s00702-020-02184-0. Epub 2020 Apr 4.
Parkinson's disease (PD) is a neurodegenerative disorder caused by a complex interplay of genetic and environmental factors. For the stratification of PD patients and the development of advanced clinical trials, including causative treatments, a better understanding of the underlying genetic architecture of PD is required. Despite substantial efforts, genome-wide association studies have not been able to explain most of the observed heritability. The majority of PD-associated genetic variants are located in non-coding regions of the genome. A systematic assessment of their functional role is hampered by our incomplete understanding of genotype-phenotype correlations, for example through differential regulation of gene expression. Here, the recent progress and remaining challenges for the elucidation of the role of non-coding genetic variants is reviewed with a focus on PD as a complex disease with multifactorial origins. The function of gene regulatory elements and the impact of non-coding variants on them, and the means to map these elements on a genome-wide level, will be delineated. Moreover, examples of how the integration of functional genomic annotations can serve to identify disease-associated pathways and to prioritize disease- and cell type-specific regulatory variants will be given. Finally, strategies for functional validation and considerations for suitable model systems are outlined. Together this emphasizes the contribution of rare and common genetic variants to the complex pathogenesis of PD and points to remaining challenges for the dissection of genetic complexity that may allow for better stratification, improved diagnostics and more targeted treatments for PD in the future.
帕金森病（PD）是一种神经退行性疾病，由遗传和环境因素的复杂相互作用引起。为了对 PD 患者进行分层，以及开展包括病因治疗在内的先进临床试验，需要更好地了解 PD 的潜在遗传结构。尽管付出了巨大努力，但全基因组关联研究仍未能解释大部分观察到的遗传率。大多数与 PD 相关的遗传变异位于基因组的非编码区域。由于我们对基因型-表型相关性的理解不完整，例如通过基因表达的差异调节，对其功能作用进行系统评估受到阻碍。本文重点介绍 PD 是一种具有多因素起源的复杂疾病，综述了非编码遗传变异作用阐明的最新进展和仍然存在的挑战。将阐述基因调控元件的功能以及非编码变异对它们的影响，以及在全基因组水平上对这些元件进行映射的方法。此外，还将举例说明如何整合功能基因组注释来识别与疾病相关的途径，并优先考虑与疾病和细胞类型特异性相关的调控变异。最后，概述了功能验证的策略和合适的模型系统的考虑因素。综上所述，这强调了罕见和常见遗传变异对 PD 复杂发病机制的贡献，并指出了在遗传复杂性剖析方面仍存在的挑战，这可能有助于未来更好地对 PD 进行分层、提高诊断水平并进行更有针对性的治疗。
