Neurodevelopmental and neuropsychiatric disorders represent an interconnected molecular system
Neurodevelopmental and neuropsychiatric disorders represent an interconnected molecular system
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DOI：
10.1038/mp.2013.16
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发表时间：
2014-03-01
影响因子：
11
通讯作者：
Claudianos, C.
中科院分区：
文献类型：
--
作者：
Cristino, A. S.;Williams, S. M.;Claudianos, C.
在不同人群的个体中，已发现许多可能导致神经发育障碍(如自闭症谱系障碍(ASDS)和X连锁智力残疾(XLID)，以及神经精神障碍(包括注意缺陷多动障碍(ADHD)和精神分裂症(SZ))的遗传因素。虽然这些疾病内部和之间存在显著的病因学异质性，但最近的数据显示，遗传因素导致了它们的共病。许多研究已经确定了这些精神健康障碍的候选基因关联，尽管这通常是以零碎的方式进行的，几乎没有考虑到内在的分子复杂性。在这里，我们试图从我们对系统水平生物学的知识中抽象出关系，以帮助理解这些疾病的独特和共同的遗传驱动因素。我们采取了一种全球和系统的方法来建立和整合与自闭症、XLID、ADHD和SZ相关的基因网络中的可用数据。利用复杂网络的概念和计算方法来研究与这些条件相关的候选基因是否通过基因调控机制、功能蛋白-蛋白质相互作用、转录因子(Tf)和微RNA(MiRNA)结合位点而相关。尽管我们的分析表明，与这四种疾病相关的遗传变异可以发生在相同的分子途径和功能域中，包括突触传递，但有一些变异模式定义了不同疾病之间的显著差异。特别令人感兴趣的是位于基因间区的DNA变异，这些区域包含转录因子或miRNA的调控位点。我们的方法提供了一个假设框架，这将有助于发现和分析与神经发育和神经精神障碍相关的候选基因。
Many putative genetic factors that confer risk to neurodevelopmental disorders such as autism spectrum disorders (ASDs) and X-linked intellectual disability (XLID), and to neuropsychiatric disorders including attention deficit hyperactivity disorder (ADHD) and schizophrenia (SZ) have been identified in individuals from diverse human populations. Although there is significant aetiological heterogeneity within and between these conditions, recent data show that genetic factors contribute to their comorbidity. Many studies have identified candidate gene associations for these mental health disorders, albeit this is often done in a piecemeal fashion with little regard to the inherent molecular complexity. Here, we sought to abstract relationships from our knowledge of systems level biology to help understand the unique and common genetic drivers of these conditions. We undertook a global and systematic approach to build and integrate available data in gene networks associated with ASDs, XLID, ADHD and SZ. Complex network concepts and computational methods were used to investigate whether candidate genes associated with these conditions were related through mechanisms of gene regulation, functional protein-protein interactions, transcription factor (TF) and microRNA (miRNA) binding sites. Although our analyses show that genetic variations associated with the four disorders can occur in the same molecular pathways and functional domains, including synaptic transmission, there are patterns of variation that define significant differences between disorders. Of particular interest is DNA variations located in intergenic regions that comprise regulatory sites for TFs or miRNA. Our approach provides a hypothetical framework, which will help discovery and analysis of candidate genes associated with neurodevelopmental and neuropsychiatric disorders.