Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, No. 106, Zhongshan 2nd Road, Guangzhou 510080, China.
The Second School of Clinical Medicine, Southern Medical University, No. 1023 Shatainan Road, Guangzhou 510515, China.
Brief Bioinform. 2024 May 23;25(4). doi: 10.1093/bib/bbae353.
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder for which current treatments are limited and drug development costs are prohibitive. Identifying drug targets for ASD is crucial for the development of targeted therapies. Summary-level data of expression quantitative trait loci obtained from GTEx, protein quantitative trait loci data from the ROSMAP project, and two ASD genome-wide association studies datasets were utilized for discovery and replication. We conducted a combined analysis using Mendelian randomization (MR), transcriptome-wide association studies, Bayesian colocalization, and summary-data-based MR to identify potential therapeutic targets associated with ASD and examine whether there are shared causal variants among them. Furthermore, pathway and drug enrichment analyses were performed to further explore the underlying mechanisms and summarize the current status of pharmacological targets for developing drugs to treat ASD. The protein-protein interaction (PPI) network and mouse knockout models were performed to estimate the effect of therapeutic targets. A total of 17 genes revealed causal associations with ASD and were identified as potential targets for ASD patients. Cathepsin B (CTSB) [odd ratio (OR) = 2.66 95, confidence interval (CI): 1.28-5.52, P = 8.84 × 10-3], gamma-aminobutyric acid type B receptor subunit 1 (GABBR1) (OR = 1.99, 95CI: 1.06-3.75, P = 3.24 × 10-2), and formin like 1 (FMNL1) (OR = 0.15, 95CI: 0.04-0.58, P = 5.59 × 10-3) were replicated in the proteome-wide MR analyses. In Drugbank, two potential therapeutic drugs, Acamprosate (GABBR1 inhibitor) and Bryostatin 1 (CASP8 inhibitor), were inferred as potential influencers of autism. Knockout mouse models suggested the involvement of the CASP8, GABBR1, and PLEKHM1 genes in neurological processes. Our findings suggest 17 candidate therapeutic targets for ASD and provide novel drug targets for therapy development and critical drug repurposing opportunities.
自闭症谱系障碍（ASD）是一种复杂的神经发育障碍，目前的治疗方法有限，药物开发成本高昂。确定 ASD 的药物靶点对于开发靶向治疗至关重要。本研究利用 GTEx 获得的表达数量性状基因座汇总数据、ROS-MAP 项目的蛋白质数量性状基因座数据以及两项 ASD 全基因组关联研究数据集进行发现和复制。我们使用孟德尔随机化（MR）、全转录组关联研究、贝叶斯共定位以及基于汇总数据的 MR 进行联合分析，以确定与 ASD 相关的潜在治疗靶点，并检查它们之间是否存在共同的因果变异。此外，还进行了途径和药物富集分析，以进一步探讨潜在机制，并总结目前用于开发治疗 ASD 药物的药理学靶点的现状。还进行了蛋白质-蛋白质相互作用（PPI）网络和小鼠敲除模型分析，以评估治疗靶点的效应。共有 17 个基因与 ASD 存在因果关联，并被鉴定为 ASD 患者的潜在治疗靶点。组织蛋白酶 B（CTSB）[比值比（OR）=2.6695，95%置信区间（CI）：1.28-5.52，P=8.84×10-3]、γ-氨基丁酸 B 型受体亚基 1（GABBR1）（OR=1.99，95%CI：1.06-3.75，P=3.24×10-2）和formin like 1（FMNL1）（OR=0.15，95%CI：0.04-0.58，P=5.59×10-3）在蛋白质组范围内的 MR 分析中得到了复制。在 Drugbank 中，两种潜在的治疗药物，Acamprosate（GABBR1 抑制剂）和 Bryostatin 1（CASP8 抑制剂）被推断为自闭症的潜在影响因子。敲除小鼠模型表明，CASP8、GABBR1 和 PLEKHM1 基因参与了神经过程。我们的研究结果为 ASD 提供了 17 个候选治疗靶点，并为治疗开发和关键药物再利用提供了新的药物靶点。
