T7 - . CNS Patterning Gene Variants May Bridge The Gap Between Autistic Symptoms And Brain Cortical Structure

Abstract

Background Abnormal cortical anatomy has been identified as a significant feature of the neuropathology of autism spectrum disorders (ASD). The CNS patterning gene, the wingless-type MMTV integration site family, member 2 (WNT2), has been shown to be associated with the risk for ASD and is essential for promoting cortical dendrite growth and dendritic spin formation. Whether the WNT2 variants are associated with clinical severity of autistic symptoms and cortical development is not yet studied. This study aims to investigate the genetic association between WNT2 variants and (1) clinical severity of ASD, and (2) the cortical thickness in individuals with ASD and typically-developing controls (TDC). Methods The genetic association study recruited 391 patients (males, 88.3%; mean age ± SD, 9.5 ± 4.4 years) diagnosed with ASD. Six tagging SNPs of WNT2 were genotyped and analyzed by their genetic association with the core symptoms of ASD. The candidate SNPs were selected for each linkage disequilibrium block across 5'-UTR to 3'-UTR. The neuroimage study included 122 patients with ASD (males, 95.8%; mean age 13.1 ± 6.4 years) and 118 TDC (males, 61.5%; man age 21.0 ± 9.7). Cortical thickness on MRI was analyzed by FreeSurfer software with 74 automatic parcellation. The main effect of each SNP and group*SNP interaction were examined for each region. Results In genetic association study, we found that the multi-locus markers of WNT2 were associated with communication problems and restricted/stereotyped behaviors in ASD. Patients who carry a specific haplotype showed more severe symptoms. In neuroimage study, we found that mean cortical thickness as well as nine cortical regions were reduced in ASD compared to TDC in a subsample with compatible sex and age (88 ASD and 51 TDC, mean age 13 years). Meanwhile, the WNT2 variants showed a main effect and an age interaction on the mean cortical thickness of bilateral hemispheres, as well as several brain regions including cingulate cortex and superior temporal cortex. Discussion In conclusion, our findings suggest that the variants of CNS patterning gene WNT2 may play a role in modulate the clinical severity and neuroimage phenotypes of ASD. Patients who carry specific WNT2 variants showed more severe communication deficits and severe stereotyped behaviors. Besides, WNT2 variants might contribute to the reduced cortical thickness found in ASD; subjects who carry specific genotype may experience accelerated cortical thinning during adolescence and early adulthood. These findings may be worth validation and further investigation.