Liggins Institute, The University of Auckland, Auckland, New Zealand.
Gene Structure and Function Laboratory, Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand.
Mov Disord. 2020 Aug;35(8):1346-1356. doi: 10.1002/mds.28144. Epub 2020 Jun 18.
GBA mutations are numerically the most significant genetic risk factor for Parkinson's disease (PD), yet these mutations have low penetrance, suggesting additional mechanisms.
The objective of this study was to determine if the penetrance of GBA in PD can be explained by regulatory effects on GBA and modifier genes.
Genetic variants associated with the regulation of GBA were identified by screening 128 common single nucleotide polymorphisms (SNPs) in the GBA locus for spatial cis-expression quantitative trail locus (supported by chromatin interactions).
We identified common noncoding SNPs within GBA that (1) regulate GBA expression in peripheral tissues, some of which display α-synuclein pathology and (2) coregulate potential modifier genes in the central nervous system and/or peripheral tissues. Haplotypes based on 3 of these SNPs delay disease onset by 5 years. In addition, SNPs on 6 separate chromosomes coregulate GBA expression specifically in either the substantia nigra or cortex, and their combined effect potentially modulates motor and cognitive symptoms, respectively.
This work provides a new perspective on the haplotype-specific effects of GBA and the genetic etiology of PD, expanding the role of GBA from the gene encoding the β-glucocerebrosidase (GCase) to that of a central regulator and modifier of PD onset, with GBA expression itself subject to distant regulation. Some idiopathic patients might possess insufficient GBA-encoded GCase activity in the substantia nigra as the result of distant regulatory variants and therefore might benefit from GBA-targeting therapeutics. The SNPs' regulatory impacts provide a plausible explanation for the variable phenotypes also observed in GBA-centric Gaucher's disease and dementia with Lewy bodies. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, LLC on behalf of International Parkinson and Movement Disorder Society.
GBA 突变是帕金森病（PD）最重要的遗传风险因素，但这些突变的外显率较低，提示存在其他机制。
本研究旨在确定 GBA 对 PD 的外显率是否可以通过对 GBA 和修饰基因的调节作用来解释。
通过筛选 GBA 基因座内的 128 个常见单核苷酸多态性（SNP），确定与 GBA 调节相关的遗传变异，这些 SNP 通过空间顺式表达定量轨迹（受染色质相互作用支持）进行筛选。
我们在 GBA 内发现了常见的非编码 SNP，这些 SNP 可以：（1）调节外周组织中的 GBA 表达，其中一些 SNP 显示α-突触核蛋白病理学；（2）中枢神经系统和/或外周组织中的潜在修饰基因进行共调节。基于这 3 个 SNP 的单倍型可使疾病发病时间延迟 5 年。此外，6 条不同染色体上的 SNP 特异性地调节黑质或皮质中的 GBA 表达，它们的共同作用可能分别调节运动和认知症状。
这项工作为 GBA 的单倍型特异性作用以及 PD 的遗传病因提供了新的视角，将 GBA 从编码β-葡糖苷酶（GCase）的基因扩展为 PD 发病的中央调节剂和修饰剂，而 GBA 表达本身受远距离调节。由于远处调节变异，一些特发性患者可能在黑质中具有不足的 GBA 编码 GCase 活性，因此可能受益于 GBA 靶向治疗。这些 SNP 的调节作用为 GBA 中心性 Gaucher 病和路易体痴呆中观察到的可变表型提供了合理的解释。© 2020 作者。运动障碍由 Wiley 期刊代表国际帕金森和运动障碍协会出版。
