Low coverage sequencing for the detection and analysis of genomic structural variants in schizophrenia

精神分裂症是一种以妄想和幻听为特征的破坏性疾病。结果通常不佳，会产生深远的社会和经济后果。目前的药物治疗是有限的，有令人痛苦的副作用，但重要的是，并不能改善所谓的精神分裂症的负面症状，如缺乏情感、言语贫乏和动力不足。有明确的证据表明，基因在导致精神分裂症中发挥了作用，但并不是以一种简单的方式；相反，许多单独的基因共同作用，增加了某人患精神分裂症的风险。这种复杂性以及其他非遗传因素也很重要的事实，使得识别此类易感基因变得困难。尽管这些基因的个体效应很小，而且不能解释精神分裂症的全部遗传因素，但最近已经开始发现这些基因。然而，同样的研究发现，在少数个体中，DNA发生了变化，这会产生更强的影响。这些变化被称为结构变异，是增加或移除整个基因的变化。每个人都有一些这样的结构变异，但某些罕见的变异似乎不仅会增加患精神分裂症的风险，还会增加患自闭症等其他疾病的风险。我们希望使用一种新的测序方法，在我们研究了多年的精神分裂症患者的大样本中找到这些结构变异。我们收集了许多关于这些患者的额外信息，如脑部扫描和心理测试。这些生物测试虽然不是诊断性的，但开始描述疾病的神经生物学基础。我们正在使用的测序方法将意味着我们能够利用我们的结果来设计一种简单的基因测试，以观察更多的精神分裂症患者并证实我们的发现。我们还可以测试患有其他疾病的患者，这些疾病的重叠与与精神分裂症相关的特定结构变异已经被发现。这样，我们就可以开始了解患有这些结构变异的患者可能会有什么临床诊断，并通过我们对精神分裂症患者的脑扫描和心理测试的研究，了解这些结构变异如何影响大脑功能。我们的研究最大的影响可能是开发新的精神分裂症动物和细胞模型系统，这些系统有可能识别新的药物靶点。

Schizophrenia is a devastating disorder characterised by delusions and auditory hallucinations. The outcome is generally poor with profound social and economic consequences. Current medication is limited and has distressing side effects but importantly does not improve what are called the negative symptoms of schizophrenia such as lack of emotion, poverty of speech and motivation. There is clear evidence that genetics plays a role in causing schizophrenia but not in a simple manner; rather many individual genes act together to increase the risk that someone may become schizophrenic. This complexity and the fact that other non genetic factors are also important have made it difficult to identify such susceptibility genes. Recently though such genes have begun to be identified although they have very small individual effects and don?t explain all the genetic contribution to schizophrenia. However, the same studies have found a change in the DNA in a few individuals which have a stronger effect. These changes are called structural variants and are changes that add or remove whole genes. Everyone has some of these structural variants but certain rare ones seem to increase risk not only for schizophrenia but for other diseases like autism as well. We want to use a new sequencing method to find these structural variants in a large sample of schizophrenic patients who we have been studying for many years. We have collected much additional information about these patients such as brain scans and psychological tests. These biological tests while not diagnostic begin to describe the neurobiological basis of the disease. The sequencing approach we are using will mean we are able to use our results to design a simple genetic test to look at more schizophrenic patients and confirm our findings. We can also test patients with other diseases for which overlap with particular structural variants associated with schizophrenia has already been found. In this way we can begin to understand what clinical diagnosis patients with these structural variants may have and through our studies of the brain scans and psychological tests of schizophrenics how these structural variants affect the functions of the brain. The greatest impact of our research is likely to be in the development of new animal and cellular model systems of schizophrenia which have the potential to identify new drug targets.