Liu Huan, Wang Shenghan, Cao Binbin, Zhu Jijun, Huang Zhifang, Li Pan, Zhang Shunjie, Liu Xian, Yu Jing, Huang Zhongting, Lv Linzhuo, Cai Fuqiang, Liu Weixin, Song Zhijian, Liu Yuxin, Pang Tao, Chang Suhua, Chen Ying, Chen Junfang, Chen Wen-Xiong
Department of Behavioral Development, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China.
The Assessment and Intervention Center for Autistic Children, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
Behav Brain Funct. 2025 Jun 7;21(1):15. doi: 10.1186/s12993-025-00278-x.
Autism spectrum disorder (ASD) presents a wide range of cognitive and language impairments. In this study, we investigated the genetic basis of non-verbal status in ASD using a comprehensive genomic approach. We identified a novel common variant, rs1944180 in CNTN5, significantly associated with non-verbal status through family-based Transmission Disequilibrium Testing. Polygenic risk score (PRS) analysis further showed that higher ASD PRS was significantly linked to non-verbal status (p = 0.034), specific to ASD and not related to other conditions such as bipolar disorder, schizophrenia and three language-related traits. Using structural equation modeling (SEM), we found two causal SNPs, rs1247761 located in KCNMA1 and rs2524290 in RAB3IL1, linking ASD with language traits. The model indicated a unidirectional effect, with ASD driving language impairments. Additionally, de novo mutations (DNMs) were found to be related with ASD and interaction between common variants and DNMs significantly impacted non-verbal status (p = 0.038). Our findings also identified 5 high-risk ASD genes, and DNMs were enriched in glycosylation-related pathways. These results offer new insights into the genetic mechanisms underlying language deficits in ASD.
自闭症谱系障碍（ASD）呈现出广泛的认知和语言障碍。在本研究中，我们使用综合基因组方法研究了ASD中非语言状态的遗传基础。通过基于家系的传递不平衡检验，我们在接触蛋白5（CNTN5）中鉴定出一个新的常见变异rs1944180，其与非语言状态显著相关。多基因风险评分（PRS）分析进一步表明，较高的ASD PRS与非语言状态显著相关（p = 0.034），这是ASD特有的，与双相情感障碍、精神分裂症和三种语言相关性状等其他疾病无关。使用结构方程模型（SEM），我们发现了两个因果单核苷酸多态性（SNP），位于大电导钙激活钾通道1（KCNMA1）中的rs1247761和RAB3相互作用蛋白样1（RAB3IL1）中的rs2524290，将ASD与语言性状联系起来。该模型表明存在单向效应，即ASD导致语言障碍。此外，发现新生突变（DNM）与ASD相关，常见变异和DNM之间的相互作用对非语言状态有显著影响（p = 0.038）。我们的研究结果还确定了5个高风险ASD基因，并且DNM在糖基化相关途径中富集。这些结果为ASD语言缺陷的遗传机制提供了新的见解。
