VIB-KU Leuven Center for Brain & Disease Research, Leuven 3000, Belgium; Department of Neurosciences, Leuven Brain Institute, KU Leuven, 3000 Leuven, Belgium.
Curr Opin Neurobiol. 2018 Feb;48:167-173. doi: 10.1016/j.conb.2017.12.015. Epub 2018 Jan 10.
Recent genome-wide association studies (GWAS) have identified numerous genetic risk variants for late-onset Alzheimer's disease (AD) and Parkinson's disease (PD). However, deciphering the functional consequences of GWAS data is challenging due to a lack of reliable model systems to study the genetic variants that are often of low penetrance and non-coding identities. Pluripotent stem cell (PSC) technologies offer unprecedented opportunities for molecular phenotyping of GWAS variants in human neurons and microglia. Moreover, rapid technological advances in whole-genome RNA-sequencing and epigenome mapping fuel comprehensive and unbiased investigations of molecular alterations in PSC-derived disease models. Here, we review and discuss how integrated studies that utilize PSC technologies and genome-wide approaches may bring new mechanistic insight into the pathogenesis of AD and PD.
最近的全基因组关联研究（GWAS）已经确定了许多与迟发性阿尔茨海默病（AD）和帕金森病（PD）相关的遗传风险变异。然而，由于缺乏可靠的模型系统来研究遗传变异，这些遗传变异通常具有低外显率和非编码特性，因此解析 GWAS 数据的功能后果具有挑战性。多能干细胞（PSC）技术为在人类神经元和小胶质细胞中对 GWAS 变异进行分子表型分析提供了前所未有的机会。此外，全基因组 RNA 测序和表观基因组图谱技术的快速发展，为 PSC 衍生疾病模型中分子改变的全面和无偏研究提供了动力。在这里，我们回顾和讨论了如何利用 PSC 技术和全基因组方法进行综合研究，为 AD 和 PD 的发病机制带来新的机制见解。
