Xie Tong, Deng Libin, Mei Puming, Zhou Yiyi, Wang Bo, Zhang Jie, Lin Jiari, Wei Yi, Zhang Xiong, Xu Renshi
Department of Neurology, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, China.
Neurobiol Aging. 2014 Jul;35(7):1778.e9-1778.e23. doi: 10.1016/j.neurobiolaging.2014.01.014. Epub 2014 Jan 17.
Sporadic amyotrophic lateral sclerosis (sALS) is a severe neurodegenerative disease that causes progressive motor neuron death. Although the etiology of sALS remains unknown, genetic variants are thought to predispose individuals to the disease. Several recent genome-wide association studies have identified a number of loci that increase sALS susceptibility, but these only explain a small proportion of the disease. To extend the current genetic evidence and to identify novel candidates of sALS, we performed a pooling genome-wide association study by 859,311 autosomal single-nucleotide polymorphisms of IlluminaHumanOmniZhongHua-8 combining pathway analysis in 250 typical sALS cases precluding age, clinical course, and phenotype interference and 250 control subjects from Chinese Han populations (CHP). The results revealed that 8 novel loci of 1p34.3, 3p21.1, 3p22.2, 10p15.2, 22q12.1, 3q13.11, 11q25, 12q24.33, and 5 previously reported loci of CNTN4 (kgp11325216), ATXN1 (kgp8327591), C9orf72 (kgp6016770), ITPR2 (kgp3041552), and SOD1 (kgp10760302) were associated with sALS from CHP. Furthermore, the pathway analysis based on the Gene Set Analysis Toolkit V2 showed that 10 top pathways were strongly associated with sALS from CHP, and among them, the 7 most potentially candidate pathways were phosphatidylinositol signaling system, Wnt signaling pathway, axon guidance, MAPK signaling pathway, neurotrophin signaling pathway, arachidonic acid metabolism, and T-cell receptor signaling pathway, a total of 39 significantly associate genes in 7 candidate pathways was suggested to involve in the pathogenesis of sALS from CHP. In conclusion, our results revealed several new loci and pathways related to sALS from CHP and extend the association evidence for partial loci, genes, and pathways, which were previously identified in other populations. Thus, our data provided new clues for exploring the pathogenesis of sALS.
散发性肌萎缩侧索硬化症（sALS）是一种严重的神经退行性疾病，可导致运动神经元进行性死亡。尽管sALS的病因尚不清楚，但遗传变异被认为会使个体易患该疾病。最近的几项全基因组关联研究已经确定了一些增加sALS易感性的基因座，但这些仅解释了该疾病的一小部分。为了扩展当前的遗传证据并识别sALS的新候选基因，我们通过对859,311个IlluminaHumanOmniZhongHua-8常染色体单核苷酸多态性进行混合全基因组关联研究，并结合通路分析，研究对象包括250例排除年龄、临床病程和表型干扰的典型sALS病例以及来自中国汉族人群（CHP）的250名对照。结果显示，1p34.3、3p21.1、3p22.2、10p15.2、22q12.1、3q13.11、11q25、12q24.33这8个新基因座以及之前报道的CNTN4（kgp11325216）、ATXN1（kgp8327591）、C9orf72（kgp6016770）、ITPR2（kgp3041552）和SOD1（kgp10760302）这5个基因座与CHP中的sALS相关。此外，基于基因集分析工具包V2的通路分析表明，10条顶级通路与CHP中的sALS密切相关，其中7条最具潜在候选性的通路为磷脂酰肌醇信号系统、Wnt信号通路、轴突导向、MAPK信号通路、神经营养因子信号通路、花生四烯酸代谢和T细胞受体信号通路，提示7条候选通路中总共39个显著相关基因参与了CHP中sALS的发病机制。总之，我们的结果揭示了几个与CHP中sALS相关的新基因座和通路，并扩展了部分基因座、基因和通路的关联证据，这些在其他人群中已有报道。因此，我们的数据为探索sALS的发病机制提供了新线索。
