Abstract
BackgroundAutism is a complex disease involving both environmental and genetic factors. Recent efforts have implicated the correlation of genomic imprinting and brain development in autism, however the pathogenesis of autism is not completely clear. Here, we used bioinformatic tools to provide a comprehensive analysis of the autism-related genes, genomic imprinted genes and the spatially and temporally differentially expressed genes of human brain, aiming to explore the relationship between autism, brain development and genomic imprinting.MethodsThis study analyzed the distribution correlation between autism-related genes and imprinted genes on chromosomes using sliding windows and statistical methods. The normal brains’ gene expression microarray data were reanalyzed to construct a spatio-temporal coordinate system of gene expression during brain development. Finally, we intersected the autism-related genes, imprinted genes and brain spatio-temporally differentially expressed genes for further analysis to find the major biological processes that these genes involved.ResultsWe found a positive correlation between the autism-related genes’ and imprinted genes’ distribution on chromosomes. Through the analysis of the normal brain microarray data, we constructed a spatio-temporal coordinate system of gene expression during human brain development, and obtained 13 genes that are differentially expressed in the process of brain development, which are both autism-related genes and imprinted genes. Furthermore, enrichment analysis illustrated that these genes are mainly involved in the biological processes, such as gamma-aminobutyric acid signaling pathway, neuron recognition, learning or memory, and regulation of synaptic transmission. Bioinformatic analysis implied that imprinted genes regulate the development and behavior of the brain. And its own mutation or changes in the epigenetic modification state of the imprinted control region could lead to some diseases, indicating that imprinted genes and brain development play an important role in diagnosis and prognosis of autism.ConclusionThis study systematically correlates brain development and genomic imprinting with autism, which provides a new perspective for the study of genetic mechanisms of autism, and selected the potential candidate biomarkers for early diagnosis of autism in clinic.
Highlights
Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders characterized by deficits in social and verbal communication, and the presence of restricted interests, stereotyped and repetitive behaviors [1]
Enrichment analysis of Gene Ontology (GO) (Fig. 1a and Table S4) showed that autism-related genes participated in multiple biological processes, mainly including synaptic transmission and regulation, nervous system development, gated channel activity, signal transduction, learning and memory and the brain development
From the view of the related diseases, we found these autism-related genes were enriched in autism, schizophrenia or other mental illness, but they were associated with attention deficit, hyperactivity, bulimia, kidney disease, homocysteinemia and other diseases (Table 2)
Summary
Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders characterized by deficits in social and verbal communication, and the presence of restricted interests, stereotyped and repetitive behaviors [1]. The etiology of ASD has not been fully identified and lacks biological markers [3] In clinic, it mainly relies on doctors’ observation of children’s behavioral characteristics and parents’ description for diagnosis, which is extremely difficult and subjective. Wang et al performed a GWAS and case-control association study on 780 families (3101 subjects) from Autism Genetic Resource Exchange (AGRE) and 8695 European individuals (1204 ASD vs 6491 control). In 2007, Sebat et al performed high-resolution genomic microarray analysis of 264 families to detect the rate of de novo CNV in ASD patients and normal subjects. It was confirmed for the first time that de novo CNVs were significantly associated with autism (P = 0.0005). We used bioinformatic tools to provide a comprehensive analysis of the autism-related genes, genomic imprinted genes and the spatially and temporally differentially expressed genes of human brain, aiming to explore the relationship between autism, brain development and genomic imprinting
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