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Abstract：
We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.
摘要：
我们提出了迄今为止最大的自闭症谱系障碍（ASD）的外显子组测序研究（n=35,584总样本，11,986与ASD）。使用增强的分析框架来整合从头和病例对照罕见变异，我们以0.1或更低的错误发现率鉴定了102个风险基因.在这些基因中，49显示在确定具有严重神经发育迟缓的个体中破坏性从头变异的频率更高，而53在确定患有ASD的个体中显示出更高的频率;将ASD病例与这些组中的突变进行比较揭示了表型差异。在大脑发育早期表达，大多数风险基因在调节基因表达或神经元通讯中发挥作用(即，突变影响神经发育和神经生理变化)，和13个落在被拷贝数变异反复击中的基因座内。在来自人类皮质的细胞中，风险基因的表达富含兴奋性和抑制性神经元谱系，与ASD潜在的兴奋性-抑制性失衡的多种途径一致。
