Autism Risk Gene CNTNAP2 Was Associated with Cingulate Anatomy in Individuals with Autism Spectrum Disorder

Background:

Contactin Associated Protein-Like 2 (CNTNAP2) has been implicated in neurodevelopmental disorders such as autism spectrum disorder (ASD). In addition to being associated with impaired development of language, CNTNAP2 may turn out to be a central node in the molecular networks controlling neurodevelopment. Evidence has shown that carriers of common variants of CNTNAP2 may have altered brain connectivity. Whether the genetic variants of CNTNAP2 are associated with cingulate structure that shows abnormal structure and function in ASD is not yet studied.

Objectives:

This study aims to investigate the association between CNTNAP2 variants and the anatomical structure of cingulate gyrus.

Methods:

We recruited 122 patients with ASD and 118 typically-developing controls. All the participants underwent brain MRI imaging. Brain volume, white matter volume, cortical thickness, and gyrification of cingulate gyrus were analyzed by FreeSurfer software with 74 automatic parcellation. Cingulate gyrus was divided into anterior, middle (anterior and posterior), and posterior cingulate (dorsal and ventral) when comparing volume, gyrification, and cortical thickness. For white matter volume comparison, cingulate gyrus was divided into rostral anterior, caudal anterior, and posterior cingulate. Five SNPs of CNTNAP2 that has been reported to be associated with ASD were genotyped. Main effect of each SNP and group*SNP interaction were examined for each region of cingulate gyrus.

Results:

Preliminary analysis showed that some candidate SNPs of CNTNAP2 may be associated with the gyrification and cortical thickness of anterior part of middle cingulate gyrus and ventral part of posterior cingulate gyrus, with significant age by SNP interaction as well as age by SNP by diagnosis interaction. There was no difference on the regional volume or white matter volume. After Bonferroni correction, the SNP main effect and age interaction remained significant on gyrification of anterior part of middle cingulate gyrus. When ASD and TD were separated, age interaction was still shown in ASD but not in TD, on the gyrification of both regions and on the cortical thickness of ventral part of posterior cingulate gyrus. However, the CNTNAP2 variants we selected were not associated with clinical severity of autistic symptoms in either ASD or TD group, measured by Social Responsiveness Scale and Social Communication Questionnaire.

Conclusions:

Our findings suggest that CNTNAP2 variants might be associated with the gyrification and cortical thickness of middle and posterior cingulate structure, particularly in ASD. These findings need validation in independent samples.