Remori Veronica, Bondi Heather, Airoldi Manuel, Pavinato Lisa, Borini Giulia, Carli Diana, Brusco Alfredo, Fasano Mauro
Department of Science and High Technology, University of Insubria, 22100 Como, Italy.
Department of Medical Sciences, University of Torino, 10126 Torino, Italy.
Int J Mol Sci. 2025 Feb 27;26(5):2078. doi: 10.3390/ijms26052078.
Autism spectrum disorder (ASD) is a complex multifactorial neurodevelopmental disorder. Despite extensive research involving genome-wide association studies, copy number variant (CNV) testing, and genome sequencing, the comprehensive genetic landscape remains incomplete. In this context, we developed a systems biology approach to prioritize genes associated with ASD and uncover potential new candidates. A Protein-Protein Interaction (PPI) network was generated from genes associated to ASD in a public database. Leveraging gene topological properties, particularly betweenness centrality, we prioritized genes and unveiled potential novel candidates (e.g., , , and ). To test this approach, a list of genes within CNVs of unknown significance, identified through array comparative genomic hybridization analysis in 135 ASD patients, was mapped onto the PPI network. A prioritized gene list was obtained through ranking by betweenness centrality score. Intriguingly, by over-representation analysis, significant enrichments emerged in pathways not strictly linked to ASD, including ubiquitin-mediated proteolysis and cannabinoid receptor signaling, suggesting their potential perturbation in ASD. Our systems biology approach provides a promising strategy for identifying ASD risk genes, especially in large and noisy datasets, and contributes to a deeper understanding of the disorder's complex genetic basis.
自闭症谱系障碍（ASD）是一种复杂的多因素神经发育障碍。尽管进行了广泛的研究，包括全基因组关联研究、拷贝数变异（CNV）检测和基因组测序，但全面的遗传图谱仍然不完整。在此背景下，我们开发了一种系统生物学方法，以对与ASD相关的基因进行优先级排序，并发现潜在的新候选基因。从公共数据库中与ASD相关的基因生成了蛋白质-蛋白质相互作用（PPI）网络。利用基因拓扑特性，特别是介数中心性，我们对基因进行了优先级排序，并揭示了潜在的新候选基因（例如， 、 和 ）。为了验证这种方法，将通过对135名ASD患者进行阵列比较基因组杂交分析确定的意义不明的CNV内的基因列表映射到PPI网络上。通过按介数中心性得分进行排序获得了一个优先级基因列表。有趣的是，通过过度表达分析，在与ASD没有严格联系的途径中出现了显著富集，包括泛素介导的蛋白水解和大麻素受体信号传导，这表明它们在ASD中可能受到干扰。我们的系统生物学方法为识别ASD风险基因提供了一种有前景的策略，特别是在大型且有噪声的数据集中，并有助于更深入地理解该疾病复杂的遗传基础。
