Discovery Neuroscience Research, Eli Lilly and Company Ltd, Windlesham, Surrey, United Kingdom.
Sidra Medical and Research Center, Doha, Qatar.
Ann N Y Acad Sci. 2016 Feb;1366(1):61-75. doi: 10.1111/nyas.13066.
The spectacular advance in our understanding of the genetic basis of schizophrenia through genome-wide association studies has the potential to identify new leads for drug treatment through improved understanding of disease pathophysiology. However, using these genetic associations successfully in drug development and patient stratification requires further target validation, particularly in understanding which gene(s) is causal in the disease, how the risk variants alter gene function and regulation, and how they fit into disease pathways and networks. If researchers consider the disease network as the target, they need to understand which genes should be targeted and in which modality, in order to modulate pathophysiology and obtain a beneficial effect for the patient. In the present article, we review recent genetic findings in schizophrenia and discuss how these might be validated with biology and integrated with epigenetic and transcriptome data to identify targets that lie within disease networks and pathways. This new understanding of disease biology will also facilitate the development of assays that recapitulate specific aspects of the disease using model organisms and cells. These assays can then be used in screening approaches, which manipulate disease networks or pathological processes to generate and test therapeutic strategies.
通过全基因组关联研究，我们对精神分裂症遗传基础的理解取得了显著进展，这有可能通过更好地了解疾病病理生理学，为药物治疗提供新的线索。然而，要成功地将这些遗传关联应用于药物开发和患者分层，需要进一步进行靶点验证，特别是在理解疾病中哪个（些）基因是因果关系，风险变异如何改变基因功能和调控，以及它们如何适应疾病途径和网络。如果研究人员将疾病网络视为靶点，他们需要了解应该针对哪些基因以及以何种方式进行靶向，以调节病理生理学并为患者带来有益的效果。在本文中，我们回顾了精神分裂症的最新遗传发现，并讨论了如何通过生物学验证以及与表观遗传学和转录组数据的整合来确定位于疾病网络和途径内的靶点。这种对疾病生物学的新理解也将有助于利用模式生物和细胞开发能够重现疾病特定方面的测定方法。然后可以使用这些测定方法进行筛选方法，这些方法可以操纵疾病网络或病理过程，以产生和测试治疗策略。
