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

用于检测和分析精神分裂症基因组结构变异的低覆盖度测序

• 批准号: G1100583/1
• 负责人: John Powell
• 金额: $ 129.45万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G1100583%2F1
• 关键词: Low; coverage; sequencing; detection; analysis

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.

精神分裂症是一种以妄想和幻听为特征的毁灭性疾病。其结果通常很差，并产生了深刻的社会和经济后果。目前的药物治疗是有限的，有令人痛苦的副作用，但重要的是不能改善所谓的精神分裂症的阴性症状，如缺乏情感，言语和动机的贫困。有明确的证据表明，遗传学在导致精神分裂症方面发挥了作用，但不是以简单的方式;而是许多个体基因共同作用，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。最近，虽然这样的基因已经开始被确定，虽然他们有非常小的个人影响和唐？无法解释精神分裂症的所有遗传因素。然而，同样的研究发现，在一些个体中，DNA的变化具有更强的影响。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，但某些罕见的结构变异似乎不仅会增加精神分裂症的风险，还会增加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。我们已经收集了很多关于这些患者的额外信息，如脑部扫描和心理测试。这些生物学测试虽然不是诊断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使用我们的结果来设计一个简单的基因测试，以查看更多的精神分裂症患者并确认我们的发现。我们还可以对患有其他疾病的患者进行测试，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，这样我们就可以开始了解患有这些结构变异的患者可能具有的临床诊断，并通过我们对精神分裂症患者的大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。我们研究的最大影响可能是开发新的精神分裂症动物和细胞模型系统，这些系统有可能确定新的药物靶点。