Convergent and distributed effects of the 3q29 deletion on the human neural transcriptome.
Convergent and distributed effects of the 3q29 deletion on the human neural transcriptome.
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DOI：
10.1038/s41398-021-01435-2
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发表时间：
2021-06-15
影响因子：
6.8
通讯作者：
Mulle JG
中科院分区：
文献类型：
--
作者：
Sefik E;Purcell RH;Emory 3q29 Project;Walker EF;Bassell GJ;Mulle JG
3q29缺失（3q29Del）赋予精神分裂症和其他神经发育和精神疾病的高风险。然而，在这段时间内，没有一个基因与疾病明确相关，这促使人们假设神经精神后遗症是在多个功能相关基因丢失后出现的。3q29基因的注释不均匀，3q29Del对人类神经转录组的影响尚不清楚。为了系统地制定关于3q29Del与神经精神疾病相关的分子机制的无偏假设，我们对非病理性成人皮质转录组进行了系统水平的网络分析，并生成了基于证据的预测，将3q29基因与新功能和疾病关联联系起来。位于间隔的21个蛋白质编码基因分离成7个高度共表达的基因簇，表明3q29Del在询问的转录组学景观中的收敛和分布效应。这些簇的通路分析表明参与神经系统功能，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，表明3q29Del生物学与特发性疾病有关。利用“内疚协会”，我们提出了九个3q29基因，包括一个枢纽基因，作为优先驱动程序的神经精神风险。这些结果为精神分裂症最大已知遗传风险因素的因果驱动因素和机制的实验分析提供了可检验的假设，并强调了非病理性死后组织中正常功能的研究，以进一步了解精神病遗传学，特别是对于罕见的综合征，如3q29Del，从携带者获得神经组织是不可用或有限的。
The 3q29 deletion (3q29Del) confers high risk for schizophrenia and other neurodevelopmental and psychiatric disorders. 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, posttranslational 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 postmortem 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.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
20.1
作者：
Chan SY;Loscalzo J
通讯作者：
Loscalzo J
影响因子：
11
作者：
Chen, C.;Cheng, L.;Grennan, K.;Pibiri, F.;Zhang, C.;Badner, J. A.;Gershon, E. S.;Liu, C.
通讯作者：
Liu, C.
影响因子：
15.8
作者：
Ahn AC;Tewari M;Poon CS;Phillips RS
通讯作者：
Phillips RS
影响因子：
11
作者：
Gordon, Aaron;Forsingdal, Annika;Geschwind, Daniel H
通讯作者：
Geschwind, Daniel H