肌萎缩侧索硬化症作为一种致命的神经退行性疾病,目前缺乏有效的治疗药物。因此,寻找新的治疗靶点来驱动疾病治疗是必要的。在这项研究中,我们利用来自全基因组关联研究的脑和血浆蛋白作为遗传工具,进行孟德尔随机化分析,以确定肌萎缩侧索硬化症的潜在药物靶点.此外,我们使用其他数据集在外部验证了我们的结果。我们还使用贝叶斯共定位分析和表型扫描。此外,我们构建了一个蛋白质-蛋白质相互作用网络,以阐明已鉴定的蛋白质与现有靶标之间的潜在相关性。孟德尔随机化分析表明ANO5水平升高(OR=1.30;95%CI,1.14-1.49;P=1.52E-04),SCFD1(OR=3.82;95%CI,2.39-6.10;P=2.19E-08),和SIGLEC9(OR=1.05;95%CI,1.03-1.07;P=4.71E-05)与肌萎缩侧索硬化症的风险增加相关,外部验证支持这些发现。共定位分析证实ANO5、SCFD1和SIGLEC9(coloc。abf-PPH4分别=0.848、0.984和0.945)与肌萎缩侧索硬化症共享相同的变体,进一步证实这些蛋白质作为治疗靶标的潜在作用。肌萎缩侧索硬化症的潜在蛋白质与现有靶标之间存在相互作用关系。我们的研究结果表明,升高的ANO5,SCFD1和SIGLEC9水平与肌萎缩侧索硬化症的风险增加有关,可能是有希望的治疗目标。然而,需要进一步探索,以充分了解所涉及的潜在机制。
Amyotrophic lateral sclerosis as a fatal neurodegenerative disease currently lacks effective therapeutic agents. Thus, finding new therapeutic targets to drive disease treatment is necessary. In this study, we utilized brain and plasma proteins as genetic instruments obtained from genome-wide association studies to conduct a Mendelian randomization analysis to identify potential drug targets for amyotrophic lateral sclerosis. Additionally, we validated our results externally using other datasets. We also used Bayesian co-localization analysis and phenotype scanning. Furthermore, we constructed a protein-protein interaction network to elucidate potential correlations between the identified proteins and existing targets. Mendelian randomization analysis indicated that elevated levels of ANO5 (OR = 1.30; 95 % CI, 1.14-1.49; P = 1.52E-04), SCFD1 (OR = 3.82; 95 % CI, 2.39-6.10; P = 2.19E-08), and SIGLEC9 (OR = 1.05; 95% CI, 1.03-1.07; P = 4.71E-05) are associated with an increased risk of amyotrophic lateral sclerosis, with external validation supporting these findings. Co-localization analysis confirmed that ANO5, SCFD1, and SIGLEC9 (coloc.abf-PPH4 = 0.848, 0.984, and 0.945, respectively) shared the same variant with amyotrophic lateral sclerosis, further substantiating potential role of these proteins as a therapeutic target. There are interactive relationships between the potential proteins and existing targets of amyotrophic lateral sclerosis. Our findings suggested that elevated levels of ANO5, SCFD1, and SIGLEC9 are connected with an increased risk of amyotrophic lateral sclerosis and might be promising therapeutic targets. However, further exploration is necessary to fully understand the underlying mechanisms involved.