Unraveling genetic risk contributions to nonverbal status in autism spectrum disorder probands

• Published in: Behavioral and brain functions Vol. 21; no. 1; pp. 15 - 11
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England BioMed Central 07.06.2025; BMC
• Subjects: Adolescent; Adult; Autism; Autism spectrum disorder; Autism Spectrum Disorder - genetics; Bipolar disorder; Child; Common variants; De Novo mutations; Families & family life; Female; Genetic Predisposition to Disease - genetics; Genomes; Genotype & phenotype; Glycosylation; Health risk assessment; Humans; Language; Male; Mental disorders; Metabolism; Multifactorial Inheritance - genetics; Mutation; Non-verbal status; Nonverbal Communication; Parents & parenting; Polygenic inheritance; Polymorphism, Single Nucleotide - genetics; Quality control; Schizophrenia; Single-nucleotide polymorphism; Whole-exome sequencing; De Novo mutations; Common variants; Whole-exome sequencing; Autism spectrum disorder; Non-verbal status
• ISSN: 1744-9081; 1744-9081
• 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.