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

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.自闭症谱系障碍（ASD）是一类兼具表型异质性与遗传异质性的神经发育障碍。既往研究已在ASD患者中报道了罕见突变与新发突变，但ASD的等位基因架构仍未明确。为评估常见变异与罕见变异在ASD发病中的作用，本研究基于人类大脑基因表达的广泛普查，构建了基因共表达网络，并鉴定出与特定细胞类型及生物学过程相关的共表达模块。通过整合已知罕见突变数据与ASD全基因组关联研究（GWAS）的结果，本研究鉴定出两个同时受罕见变异与常见变异扰动的神经元共表达模块。上述模块内包含大量高度连通的基因，这些基因参与突触形成与神经元可塑性过程，且在与学习记忆、感官感知相关的脑区中表达。常见风险变异的富集现象在另外两个队列（涵盖单病例家庭与多病例家庭）中得到重复验证。针对神经元共表达模块内常见变异的联合贡献分析显示，ASD发病风险存在多基因遗传基础。本研究结果表明，神经元基因的两个子网络中出现的轻度与重度扰动，共同构成了ASD发病风险的重要贡献因素。