BACKGROUND 22q11.2 copy number variants are among the most highly penetrant genetic risk variants for developmental neuropsychiatric disorders such as schizophrenia (SCZ) and autism spectrum disorder (ASD). However, the specific mechanisms through which they confer risk remain unclear. METHODS Using a functional genomics approach, we integrated transcriptomic data from the developing human brain, genome-wide association findings for SCZ and ASD, protein interaction data, and gene expression signatures from SCZ and ASD postmortem cortex to 1) organize genes into the developmental cellular and molecular systems within which they operate, 2) identify neurodevelopmental processes associated with polygenic risk for SCZ and ASD across the allelic frequency spectrum, and 3) elucidate pathways and individual genes through which 22q11.2 copy number variants may confer risk for each disorder. RESULTS Polygenic risk for SCZ and ASD converged on partially overlapping neurodevelopmental modules involved in synaptic function and transcriptional regulation, with ASD risk variants additionally enriched for modules involved in neuronal differentiation during fetal development. The 22q11.2 locus formed a large protein network during development that disproportionately affected SCZ-associated and ASD-associated neurodevelopmental modules, including loading highly onto synaptic and gene regulatory pathways. SEPT5, PI4KA, and SNAP29 genes are candidate drivers of 22q11.2 synaptic pathology relevant to SCZ and ASD, and DGCR8 and HIRA are candidate drivers of disease-relevant alterations in gene regulation. CONCLUSIONS This approach offers a powerful framework to identify neurodevelopmental processes affected by diverse risk variants for SCZ and ASD and elucidate mechanisms through which highly penetrant, multigene copy number variants contribute to disease risk.

中文翻译：

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精神分裂症、自闭症和 22q11.2 CNV 介导的神经精神疾病风险的突触和基因调控机制

背景 22q11.2 拷贝数变异是精神分裂症 (SCZ) 和自闭症谱系障碍 (ASD) 等发育性神经精神疾病的最高外显遗传风险变异之一。然而，它们赋予风险的具体机制仍不清楚。方法使用功能基因组学方法，我们将来自发育中的人类大脑的转录组数据、SCZ 和 ASD 的全基因组关联发现、蛋白质相互作用数据以及来自 SCZ 和 ASD 死后皮层的基因表达特征整合到 1) 将基因组织到发育细胞中和它们运作的分子系统，2) 在等位基因频谱中识别与 SCZ 和 ASD 的多基因风险相关的神经发育过程，以及 3) 阐明 22q11. 2 个拷贝数变异可能为每种疾病带来风险。结果 SCZ 和 ASD 的多基因风险集中在涉及突触功能和转录调节的部分重叠的神经发育模块上，ASD 风险变异还丰富了涉及胎儿发育过程中神经元分化的模块。22q11.2 基因座在发育过程中形成了一个大的蛋白质网络，它不成比例地影响了 SCZ 相关和 ASD 相关的神经发育模块，包括高度加载到突触和基因调控通路上。SEPT5、PI4KA 和 SNAP29 基因是与 SCZ 和 ASD 相关的 22q11.2 突触病理学的候选驱动因素，而 DGCR8 和 HIRA 是与疾病相关的基因调控改变的候选驱动因素。