Networks of Neuronal Genes Affected by Common and Rare Variants in Autism Spectrum Disorders

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. Autism spectrum disorders (ASD) are neurodevelopmental syndromes with a strong genetic basis, but are influenced by many different genes. Recent studies have identified multiple genetic risk factors, including rare mutations and genetic variations common in the population. To identify possible connections between different genetic risk factors, we constructed a network based on the expression pattern of genes across different brain areas. We identified groups of genes that are expressed in a similar pattern across the brain, suggesting that they are involved in the same processes or types of cells. We found that the genetic risk factors were enriched in specific groups of connected genes. Of these, the strongest enrichment was discovered in a group of neuronal genes that are involved in processes of learning and memory, and are highly expressed during infancy. Further study of this group of genes has the potential to reveal a more detailed picture of the neuronal mechanisms leading to ASD and to provide knowledge required for developing diagnostic tools and effective therapies.