Hertie-Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, and German Center for Neurodegenerative Diseases, Tübingen, Germany.
Mov Disord. 2011 May;26(6):1042-8. doi: 10.1002/mds.23637.
Over the last 25 years, genetic findings have profoundly changed our views on the etiology of Parkinson's disease. Linkage studies and positional cloning strategies have identified mutations in a number of genes that cause several monogenic autosomal-dominant or autosomal-recessive forms of the disorder. Although most of these Mendelian forms of Parkinson's disease are rare, whole-genome association studies have more recently provided convincing evidence that low-penetrance variants in at least some of these, but also in several other genes, play a direct role in the etiology of the common sporadic disease as well. In addition, rare variants with intermediate-effect strengths in genes such as Gaucher's disease-associated glucocerebrosidase A have been discovered as important risk factors. "Next-generation" sequencing technologies are expected by some to identify many more of these variants. Thus, an increasingly complex network of genes contributing in different ways to disease risk and progression is emerging. These findings may provide the "genetic entry points" to identify molecular targets and readouts necessary to design rational disease-modifying treatments.
在过去的 25 年中，遗传发现极大地改变了我们对帕金森病病因的看法。连锁研究和定位克隆策略已经确定了一些导致几种单基因常染色体显性或常染色体隐性疾病的基因突变。尽管这些孟德尔形式的帕金森病大多数很少见，但全基因组关联研究最近提供了令人信服的证据，表明这些基因中的至少一些以及其他几个基因中的低外显率变体也直接参与了常见散发性疾病的病因。此外，在葡萄糖脑苷脂酶 A 等与戈谢病相关的基因中发现了具有中等效应强度的罕见变体，它们是重要的风险因素。一些人预计“下一代”测序技术将能够识别出更多的这些变体。因此，一个越来越复杂的基因网络正在出现，这些基因以不同的方式对疾病风险和进展做出贡献。这些发现可能为确定设计合理的疾病修饰治疗所需的分子靶标和读出物提供“遗传切入点”。
