Objectives: Autism is a severe neurodevelopmental disorder. Many susceptible or causative genes have been identified, and most of them are related to synaptogenesis. The THBS1 gene encodes thrombospondin 1, which plays a critical role in synaptogenesis of the central nervous system in the developing brain. However, no study has been carried out revealing that THBS1 is an autism risk gene.
Methods: We analyzed the whole coding region and the 5'-untranslated region of the THBS1 gene in 313 autistic patients by Sanger sequencing, which was also used to analyze the identified variants in 350 normal controls. Association analysis was carried out using PLINK or R. Haplotype analysis was carried out using Haploview. Functional prediction and conservation analysis of missense variants were carried out using ANNOVAR.
Results: Twelve variants, including five common variants and seven rare variants, were identified in the THBS1 coding region and the 5'-untranslated region. Among them, one common variant (c.1567A>G:p.T523A) was significantly associated with autism (P<0.05). Two rare variants (c.2429G>A:p.R810Q, c.3496G>C:p.E1166Q) were absent in the 350 controls and were not reported in the single nucleotide polymorphism database (dbSNP). Combined association analysis of the rare variants (minor allele frequency<0.01) in patients and Asian samples in the 1000 genome project revealed a significant association between these rare variants and autism (P=0.039).
Conclusion: Our data revealed that both common and rare variants of the THBS1 gene are associated with risk for autism, suggesting that THBS1 is a novel susceptible gene for autism.