Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism
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DOI：
10.1016/j.cell.2019.12.036
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发表时间：
2020-02-06
期刊：
影响因子：
64.5
通讯作者：
Walters, Raymond K.
中科院分区：
文献类型：
--
作者：
Satterstrom, F. Kyle;Kosmicki, Jack A.;Walters, Raymond K.
我们提出了迄今为止最大的自闭症谱系障碍（ASD）外显子组测序研究（n = 35，584总样本，11，986 ASD）。利用一个增强的分析框架，整合从头和病例对照罕见变异，我们确定了102个风险基因，错误发现率为0.1或更低，其中49个基因在被确定患有严重神经发育迟缓的个体中显示出较高的破坏性从头变异频率，而53个基因在被确定患有ASD的个体中显示出较高的频率;将ASD病例与这些组中的突变进行比较揭示了表型差异。大多数风险基因在大脑发育的早期表达，在基因表达或神经元通讯的调节中起作用（即，突变影响神经发育和神经生理学变化），13个落在拷贝数变异体反复命中的基因座内。在来自人类皮层的细胞中，风险基因的表达在兴奋性和抑制性神经元谱系中富集，这与ASD潜在的兴奋性-抑制性失衡的多个途径一致。
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 neuro-developmental 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.