Protein-Altering Variants' Analysis in Autism Subgroups Uncovers Early Brain-Expressed Gene Modules Relevant to Autism Pathophysiology

IF 5.6 2区 医学 Q1 BEHAVIORAL SCIENCES
Autism Research Pub Date : 2025-07-15 DOI:10.1002/aur.70086
Gaia Scaccabarozzi, Luca Fumagalli, Maddalena Mambretti, Roberto Giorda, Marco Villa, Silvia Busti Ceccarelli, Laura Villa, Elisa Mani, Maria Nobile, Massimo Molteni, Uberto Pozzoli, Alessandro Crippa
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Abstract

Understanding the functional implications of genes' variants in autism heterogeneity is challenging. Gene set analysis examines the cumulative effect of multiple functionally converging genes. Here we explored whether a multi-step analysis could identify gene sets with different loads of protein-altering variants (PAVs) between two subgroups of autistic children. After subdividing our sample (n = 71, 3–12 years) based on higher (> 80; n = 43) and lower ( 80; n = 28) intelligence quotient (IQ), a gene set variant enrichment analysis identified gene sets with significantly different incidence of PAVs between the two subgroups of autistic children. Significant gene sets were then clustered into modules of genes. Their brain expression was investigated according to the BrainSpan Atlas of the Developing Human Brain. Next, we extended each module by selecting the genes that were spatio-temporally co-expressed in the developing brain and physically interacting with those in modules. Last, we explored the incidence of autism susceptibility genes within original and extended modules. Our analysis identified 38 significant gene sets (FDR, q < 0.05). They clustered in four modules involved in ion cell communication, neurocognition, gastrointestinal function, and immune system. Those modules were highly expressed in specific brain structures across development. Spatio-temporal brain co-expression and physical interactions identified extended genes' clusters with over-represented autism susceptibility genes. Overall, our unbiased approach identified modules of genes functionally relevant to autism pathophysiology, possibly implicating them in phenotypic variability across subgroups. The findings also suggest that autism diversity likely originates from multiple interacting pathways. Future research could leverage this approach to identify genetic pathways relevant to autism subtyping.

Abstract Image

自闭症亚群中蛋白质改变变异的分析揭示了与自闭症病理生理相关的早期脑表达基因模块。
理解自闭症异质性中基因变异的功能含义是具有挑战性的。基因集分析检验了多个功能趋同基因的累积效应。在这里,我们探讨了多步骤分析是否可以识别自闭症儿童两个亚组之间具有不同负载的蛋白质改变变体(pav)的基因集。在细分我们的样本(n = 71,3 -12年)后,基于更高(bbb80;N = 43)和更低(≤$$ \leqslant $$ 80;n = 28)智商(IQ),基因集变异富集分析发现两个自闭症亚组之间pav发生率显著不同的基因集。然后将重要的基因集聚集到基因模块中。他们的大脑表达是根据人脑发育的脑跨度图谱来研究的。接下来,我们通过选择在发育中的大脑中时空共表达并与模块中的基因物理相互作用的基因来扩展每个模块。最后,我们探讨了原始模块和扩展模块中自闭症易感基因的发生率。我们的分析确定了38个重要的基因集(FDR, q
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来源期刊
Autism Research
Autism Research 医学-行为科学
CiteScore
8.00
自引率
8.50%
发文量
187
审稿时长
>12 weeks
期刊介绍: AUTISM RESEARCH will cover the developmental disorders known as Pervasive Developmental Disorders (or autism spectrum disorders – ASDs). The Journal focuses on basic genetic, neurobiological and psychological mechanisms and how these influence developmental processes in ASDs.
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