Unveiling promising drug targets for autism spectrum disorder: insights from genetics, transcriptomics, and proteomics

自闭症谱系障碍 全基因组关联研究 表达数量性状基因座 生物 计算生物学 孟德尔随机化 神经发育障碍 药物数据库 遗传学 生物信息学 药品 医学 自闭症 基因 药理学 单核苷酸多态性 基因型 精神科 遗传变异
作者
Rui Jiang,Wentao Huang,Xinqi Qiu,Jianyi Chen,Ruibang Luo,Ruijie Zeng,Shuangshuang Tong,Yanlin Lyu,Panpan Sun,Qizhou Lian,Felix W. Leung,Yufeng Liu,Weihong Sha,Hao Chen
出处
期刊:Briefings in Bioinformatics [Oxford University Press]
卷期号:25 (4)
标识
DOI:10.1093/bib/bbae353
摘要

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.
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