1 Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Qingdao 266071, China ; 2 College of Medicine and Pharmaceutics, Ocean University of China, Qingdao 266071, China ; 3 Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao 266071, China.
Ann Transl Med. 2014 Dec;2(12):125. doi: 10.3978/j.issn.2305-5839.2014.11.11.
Genetic risk factors that underlie many rare and common neurological diseases remain poorly understood because of the multi-factorial and heterogeneous nature of these disorders. Although genome-wide association studies (GWAS) have successfully uncovered numerous susceptibility genes for these diseases, odds ratios associated with risk alleles are generally low and account for only a small proportion of estimated heritability. These results implicated that there are rare (present in <5% of the population) but not causative variants exist in the pathogenesis of these diseases, which usually have large effect size and cannot be captured by GWAS. With the decreasing cost of next-generation sequencing (NGS) technologies, whole-genome sequencing (WGS) and whole-exome sequencing (WES) have enabled the rapid identification of rare variants with large effect size, which made huge progress in understanding the basis of many Mendelian neurological conditions as well as complex neurological diseases. In this article, recent NGS-based studies that aimed to investigate genetic causes for neurological diseases, including Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, stroke, amyotrophic lateral sclerosis and spinocerebellar ataxias, have been reviewed. In addition, we also discuss the future directions of NGS applications in this article.
遗传风险因素是许多罕见和常见神经疾病的基础，但由于这些疾病具有多因素和异质性的特点，因此仍了解甚少。尽管全基因组关联研究（GWAS）成功地发现了许多这些疾病的易感基因，但与风险等位基因相关的优势比通常较低，仅占估计遗传率的一小部分。这些结果表明，这些疾病的发病机制中存在罕见（存在于<5%的人群中）但并非致病的变异，这些变异通常具有较大的效应大小，无法通过 GWAS 捕获。随着下一代测序（NGS）技术成本的降低，全基因组测序（WGS）和全外显子组测序（WES）已经能够快速识别具有较大效应大小的罕见变异，这在理解许多孟德尔神经疾病以及复杂神经疾病的基础方面取得了巨大进展。在本文中，回顾了最近基于 NGS 的研究，这些研究旨在探讨神经疾病的遗传原因，包括阿尔茨海默病、帕金森病、癫痫、多发性硬化症、中风、肌萎缩侧索硬化症和脊髓小脑共济失调。此外，我们还在本文中讨论了 NGS 应用的未来方向。
