Department of Computer Engineering, Dongguk University, Seoul 04620, Korea.
Department of Life Science, Dongguk University, Seoul 04620, Korea.
Int J Mol Sci. 2021 Mar 22;22(6):3216. doi: 10.3390/ijms22063216.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative neuromuscular disease. Although genome-wide association studies (GWAS) have successfully identified many variants significantly associated with ALS, it is still difficult to characterize the underlying biological mechanisms inducing ALS. In this study, we performed a transcriptome-wide association study (TWAS) to identify disease-specific genes in ALS. Using the largest ALS GWAS summary statistic (n = 80,610), we identified seven novel genes using 19 tissue reference panels. We conducted a conditional analysis to verify the genes' independence and to confirm that they are driven by genetically regulated expressions. Furthermore, we performed a TWAS-based enrichment analysis to highlight the association of important biological pathways, one in each of the four tissue reference panels. Finally, utilizing a connectivity map, a database of human cell expression profiles cultured with bioactive small molecules, we discovered functional associations between genes and drugs to identify 15 bioactive small molecules as potential drug candidates for ALS. We believe that, by integrating the largest ALS GWAS summary statistic with gene expression to identify new risk loci and causal genes, our study provides strong candidates for molecular basis experiments in ALS.
肌萎缩侧索硬化症（ALS）是一种神经退行性肌肉疾病。尽管全基因组关联研究（GWAS）已经成功鉴定出许多与 ALS 显著相关的变体，但仍难以描述导致 ALS 的潜在生物学机制。在这项研究中，我们进行了转录组全关联研究（TWAS），以鉴定 ALS 中的疾病特异性基因。使用最大的 ALS GWAS 汇总统计数据（n = 80,610），我们在 19 个组织参考面板中发现了七个新基因。我们进行了条件分析以验证基因的独立性，并确认它们是由遗传调控表达驱动的。此外，我们进行了基于 TWAS 的富集分析，以突出重要生物学途径的关联，每个组织参考面板都有一个。最后，利用一个连接图，一个含有生物活性小分子培养的人类细胞表达谱数据库，我们发现了基因和药物之间的功能关联，以鉴定 15 种生物活性小分子作为 ALS 的潜在药物候选物。我们相信，通过将最大的 ALS GWAS 汇总统计数据与基因表达相结合，以鉴定新的风险基因座和因果基因，我们的研究为 ALS 的分子基础实验提供了强有力的候选基因。
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