Common Genetic Variants in TRIO Are Associated With Autism in Chinese Han Population

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders with high heritability. Nevertheless, the involvement of genetic variants in ASDs is not fully understood. One gene of interest is TRIO, which encodes a large protein that aids in GDP-to-GTP exchange as a Ras homologous (Rho) guanine nucleotide exchange factor (GEF), facilitating cytoskeleton reorganization. Thus, it plays crucial roles in neuronal migration, neurite outgrowth, and synaptic transmission. De novo mutations in TRIO have been extensively reported in the pathogenesis of ASDs. However, no evidence currently supports the genetic association between common variants in TRIO and ASDs. To investigate the role of common genetic variations in autism risk, we analyzed 12 tagging single-nucleotide polymorphisms (SNPs) in the TRIO gene. These tagging SNPs captured an average of 75% of all common variations in TRIO with a minor allele frequency (MAF) > 5%. Using the family-based association study in 239 Chinese Han autism trios, we identified the significant association of three SNPs (rs32593, rs33005, and rs27479) with autism. To confirm the association, the sample size was expanded to 427 trios by recruiting 188 additional trios. Our findings across all 427 trios confirmed that A allele of rs32593, G allele of rs33005, and C allele of rs27479 showed a preferential transmission to the affected offspring (rs32593: A > G, Z = 2.600, p=0.0093; rs33005: G > T, Z = 2.978, p=0.0029; rs27479: C > A, Z = 3.214, p=0.0013) after Bonferroni’s correction (p<0.0042). Haplotype analyses showed that one haplotype (A-G) constructed from rs32593 and rs33005 was significantly associated with autism (p=0.0064; Global p=0.022). These results suggested that the common variants in TRIO might be involved in the susceptibility to autism in the Chinese Han population.