Genes Associated With Cortical Volume Alteration In Autism Spectrum Disorder And Their Expression Profiles

Objective:Autism spectrum disorder(ASD)is a neurodevelopmental disorder that affects up to 1%of children.The core symptoms of ASD are stereotyped behaviors,difficulties in social interaction and communication,however,the disease still has clinical and neuroimaging heterogeneity.Taking the cerebral cortical volume(CCV)as an example,although most studies have reported significant differences between ASD patients and healthy controls,the reported brain regions and trends show a high degree of heterogeneity.Thus,large sample data and reliable analytic methods are needed to identify common CCV changes in ASD.In addition,we further want to know CCV difference(Δ CCV)related genes between ASD patients and healthy controls.Subjects and Methods:In this study,sample-wise transcription-neuroimaging association analyses were performed to identify genes associated with CCV changes in ASD.Here,brain gene expression data of each sample were obtained from two donated brains provided by Allen Human Brain Atlas(AHBA),and Δ CCV and CCV of each sample were calculated based on neuroimaging data of ASD patients and healthy controls..The CCV-related genes were identified by spatial Pearson correlation between gene expression and CCV;and the Δ CCV-related genes were identified by spatial Pearson correlation between gene expression and Δ CCV.Only genes satisfying the following three criteria were considered to be associated with Δ CCV in ASD:(1)Gene expression showed significant correlation with Δ CCV derived from the meta-analysis of the CCV difference between ASD patients and healthy controls;(2)Gene expression showed significant correlation with Δ CCV from all the five centers of the Autism Brain Imaging Data Exchange-I(ABIDE-1)database;(3)Gene expression showed significant correlation with CCV in more than 95%of patients and 95%of controls in ABIDE-II databaseResults:1.30 studies were finally included in meta-analysis,including 809 ASD patients and 812 healthy controls.2133 genes showed significant correlations with ΔCCV in ASD derived from the meta-analysis.2.Case-control pairs from five independent ABIDE-I centers(a total of 191 ASD patients and 191 healthy controls)were used for transcription-neuroimaging association analyses,There were 122 genes with significant correlations between gene expression and ΔCCV in all of the five centers.3.A total of 404 ASD patients and 496 healthy controls from ABIDE-Ⅱ database were included to perform individual-level sample-wise spatial correlations between gene expression and CCV,respectively.There were 482 and 892 genes with significant correlations in more than 95%individuals of ASD and health controls.4.Converging evidence from the three independent analyses revealed 33 genes with stable association with ΔCCV between patients with ASD and healthy controls.5.The identified 33 genes were significantly enriched for cell components of ion channel,neuron projection,transporter complex and synapse,and expression levels of these genes were significantly correlated with brain activation distributions of neural processes frequently impaired in ASD.Conclusion:This study aimed to search for the transcriptionally conserved genes related to CCV differences in ASD patients,and further to understand the functional and molecular mechanisms of these genes.These findings indicate that cerebral cortical volumetric changes in ASD are associated with genes related to important neuronal functions and ASD-related brain activities.