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毁灭性疾病。结果通常很糟糕，会产生深远的社会和经济后果。目前的药物是有限的，有令人痛苦的副作用，但重要的是不能改善所谓的精神分裂症的负面症状，如缺乏情感，语言和动力贫乏。有明确的证据表明，基因在导致精神分裂症中起作用，但不是以一种简单的方式；相反，许多个体基因共同作用会增加患精神分裂症的风险。这种复杂性和其他非遗传因素也很重要的事实使得很难确定这种易感基因。最近，尽管这些基因已经开始被识别出来，尽管它们对个体的影响很小。解释精神分裂症的所有遗传因素。然而，同样的研究发现，少数人的DNA变化会产生更强的影响。这些变化被称为结构变异，是增加或删除整个基因的变化。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。我们想用一种新的测序方法在我们研究多年的大量精神分裂症患者样本中找到这些结构变异。我们已经收集了很多关于这些病人的额外信息，比如脑部扫描和心理测试。这些生物学测试虽然不能诊断，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设计一个简单的基因测试来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，这些疾病与已经发现的与精神分裂症相关的特定结构变异重叠。通过这种方式，我们可以开始了解患有这些结构变异的患者的临床诊断，并通过我们对精神分裂症患者的脑部扫描和心理测试的研究，了解这些结构变异是如何影响大脑功能的。我们的研究最大的影响可能是在精神分裂症的新的动物和细胞模型系统的发展，这有可能确定新的药物靶点。

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.