The 3q29 deletion (3q29Del) confers >40-fold increased risk for schizophrenia. However, no single gene in this interval is definitively associated with disease, prompting the hypothesis that neuropsychiatric sequelae emerge upon loss of multiple functionally-connected genes. 3q29 genes are unevenly annotated and the impact of 3q29Del on the human neural transcriptome is unknown. To systematically formulate unbiased hypotheses about molecular mechanisms linking 3q29Del to neuropsychiatric illness, we conducted a systems-level network analysis of the non-pathological adult human cortical transcriptome and generated evidence-based predictions that relate 3q29 genes to novel functions and disease associations. The 21 protein-coding genes located in the interval segregated into seven clusters of highly co-expressed genes, demonstrating both convergent and distributed effects of 3q29Del across the interrogated transcriptomic landscape. Pathway analysis of these clusters indicated involvement in nervous-system functions, including synaptic signaling and organization, as well as core cellular functions, including transcriptional regulation, post-translational modifications, chromatin remodeling and mitochondrial metabolism. Top network-neighbors of 3q29 genes showed significant overlap with known schizophrenia, autism and intellectual disability-risk genes, suggesting that 3q29Del biology is relevant to idiopathic disease. Leveraging guilt by association, we propose nine 3q29 genes, including one hub gene, as prioritized drivers of neuropsychiatric risk. These results provide testable hypotheses for experimental analysis on causal drivers and mechanisms of the largest known genetic risk factor for schizophrenia and highlight the study of normal function in non-pathological post-mortem tissue to further our understanding of psychiatric genetics, especially for rare syndromes like 3q29Del, where access to neural tissue from carriers is unavailable or limited.

中文翻译：

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精神分裂症相关的3q29缺失对人类神经转录组的收敛和分布效应。

3q29缺失（3q29Del）使精神分裂症的风险增加40倍以上。然而，在这个间隔中没有一个基因明确地与疾病相关，这提示了一个假设，即失去多个功能相关的基因后，就会出现神经精神后遗症。3q29基因的注释不均，并且3q29Del对人类神经转录组的影响尚不清楚。为了系统地表达关于将3q29Del与神经精神疾病联系起来的分子机制的无偏假设，我们对非病理性成人皮层转录组进行了系统级的网络分析，并生成了基于证据的预测，将3q29基因与新功能和疾病关联相关联。位于该区间的21个蛋白质编码基因被分成7个高度共表达的基因簇，展示了3q29Del在整个转录组中的收敛和分布效应。对这些簇的通路分析表明，它们参与了神经系统功能，包括突触信号传导和组织，以及核心细胞功能，包括转录调控，翻译后修饰，染色质重塑和线粒体代谢。3q29基因的顶级网络邻居显示与已知的精神分裂症，自闭症和智力残疾风险基因显着重叠，这表明3q29Del生物学与特发性疾病有关。利用关联的内感，我们提出了9个3q29基因，包括1个中枢基因，作为神经精神病风险的优先驱动因素。