Abstract
Autism spectrum disorders (ASD) are neurodevelopmental disorders with phenotypic and genetic heterogeneity. Recent studies have reported rare and de novo mutations in ASD, but the allelic architecture of ASD remains unclear. To assess the role of common and rare variations in ASD, we constructed a gene co-expression network based on a widespread survey of gene expression in the human brain. We identified modules associated with specific cell types and processes. By integrating known rare mutations and the results of an ASD genome-wide association study (GWAS), we identified two neuronal modules that are perturbed by both rare and common variations. These modules contain highly connected genes that are involved in synaptic and neuronal plasticity and that are expressed in areas associated with learning and memory and sensory perception. The enrichment of common risk variants was replicated in two additional samples which include both simplex and multiplex families. An analysis of the combined contribution of common variants in the neuronal modules revealed a polygenic component to the risk of ASD. The results of this study point toward contribution of minor and major perturbations in the two sub-networks of neuronal genes to ASD risk.
Highlights
Autism is the most severe end of a group of neurodevelopmental disorders referred to as autism spectrum disorders (ASDs)
Can we identify gene networks that are perturbed by rare variations that in turn lead to ASD? Second, can we identify gene networks that are perturbed by common variations? Third, do rare and common variations converge on the same molecular pathways or do they represent diverse biological etiologies? Lastly, can we integrate the gene network with genome-wide association studies (GWAS) results to predict potential genes associated with ASD? To answer these questions we integrated the co-expression network with the results of autism GWAS and with known rare mutations
We tested the modules for enrichment of specific neural cell populations based on gene expression levels in neurons, astrocytes and oligodendrocytes, as found in a survey performed on mouse brain cells [21]
Summary
Autism is the most severe end of a group of neurodevelopmental disorders referred to as autism spectrum disorders (ASDs). Previous studies have identified both common and rare variants, including de novo mutations, as risk factors for ASD [4,5]. An increasing number of studies have shown that rare and de novo mutations contribute to ASD [8,9,10,11,12]. These rare variants include mutations causing single-gene disorders, cytogenetically visible chromosomal abnormalities, and more recently the identification of rare and de-novo copy number variations (CNVs) [8,9,10,12]. Other findings that further complicate the interpretation and utilization of rare variants is the fact that many of the same variants have been found in patients with distinct illnesses (such as schizophrenia, epilepsy, and intellectual disability), as well as in healthy family members or controls [14]
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