networks of neuronal genes affected by common and rare variants in autism spectrum disorders神经网络的基因影响自闭症谱系障碍的常见和罕见变异.pdfVIP

Networks of Neuronal Genes Affected by Common and Rare Variants in Autism Spectrum Disorders Eyal Ben-David, Sagiv Shifman* Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel 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. Citation: Ben-David E, Shifman S (2012) Networks of Neuronal Genes Affected by Common and Rare Variants in Autism Spectrum Disorders. PLoS Genet 8(3): e1002556. doi:10.1371/journal.pgen.1002556 Editor: Greg Gibson, Georgia Institute of Technology, United States of America Received October 4, 2011; Accepted January 11, 2012; Published March 8, 2012 Cop