Medical Research Council Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, United Kingdom.
Biol Psychiatry. 2012 Aug 15;72(4):311-7. doi: 10.1016/j.biopsych.2011.12.031. Epub 2012 Apr 12.
Despite high heritability, the genetic variants influencing bipolar disorder (BD) susceptibility remain largely unknown. Low statistical power to detect the small effect-size alleles believed to underlie much of the genetic risk and possible heterogeneity between cohorts are an increasing concern. Integrative biology approaches might offer advantages over genetic analysis alone by combining different genomic datasets at the higher level of biological processes rather than the level of specific genetic variants or genes. We employed this strategy to identify biological processes involved in BD etiopathology.
Three genome-wide association studies and a brain gene-expression study were combined with the Human Protein Reference Database protein-protein interaction network data. We used bioinformatic analysis to search for biological networks with evidence of association on the basis of enrichment among both genetic and differential-expression associations with BD.
We identified association with gene networks involved in transmission of nerve impulse, Wnt, and Notch signaling. Three features stand out among these genes: 1) they localized to the human postsynaptic density, which is crucial for neuronal function; 2) their mouse knockouts present altered behavioral phenotypes; and 3) some are known targets of the pharmacological treatments for BD.
Genetic and gene-expression associations of BD cluster in discrete regions of the protein-protein interaction network. We found replicated evidence for association for networks involving several interlinked signaling pathways. These genes are promising candidates to generate animal models and pharmacological interventions. Our results demonstrate the potential advantage of integrative biology analyses of BD datasets.
尽管双相情感障碍（BD）的遗传易感性具有很高的遗传性，但影响其易感性的遗传变异仍然很大程度上未知。检测被认为是遗传风险的大部分基础的小效应等位基因的统计能力较低，并且队列之间可能存在异质性，这是一个日益令人关注的问题。综合生物学方法可能优于仅通过遗传分析提供优势，因为它可以在更高的生物学过程水平上而不是在特定遗传变异或基因水平上结合不同的基因组数据集。我们采用了这种策略来识别与 BD 发病机制相关的生物学过程。
将三项全基因组关联研究和一项大脑基因表达研究与人类蛋白质参考数据库蛋白质-蛋白质相互作用网络数据相结合。我们使用生物信息学分析来搜索具有关联证据的生物学网络，依据是与 BD 的遗传和差异表达关联均具有富集性。
我们确定了与涉及神经冲动传递、Wnt 和 Notch 信号转导的基因网络有关联。这些基因中有三个特征突出：1）它们定位于人类突触后密度区，这对于神经元功能至关重要；2）它们的小鼠敲除体表现出改变的行为表型；3）其中一些是 BD 药物治疗的已知靶点。
BD 的遗传和基因表达关联在蛋白质-蛋白质相互作用网络的离散区域中聚集。我们发现了与涉及几个相互关联的信号通路的网络关联的重复证据。这些基因是生成动物模型和药物干预的有希望的候选物。我们的结果表明，对 BD 数据集进行综合生物学分析具有潜在优势。
