A genome-wide association study of psychosis and its characteristic endophenotypes

精神疾病影响2%的人口，是导致残疾的七大原因之一（WHO）。虽然精神障碍在家庭和neuregulin 1和dysbindin运行是有前途的候选基因，明确的风险基因仍然难以捉摸。全基因组关联允许在大样本中测试整个人类基因组中的数十万个标记，并已成功识别出糖尿病和心脏病等70种常见疾病的近200个基因。然而，精神病诊断并不构成遗传研究的简单特征，我建议使用生物标志物作为替代。这些生物标志物是通过实验室方法获得的表征精神病的定量生物学特征。本项目的目的是使用全基因组扫描来检查遗传变异与（iii）精神病（在传统的病例对照设计中）（iv）疾病特征性脑功能或结构的生物标志物之间的关联。我们的建议从双胞胎和家庭研究中，我选择了最合适的精神病生物标志物。这些包括记忆和其他认知能力的缺陷，以及通过EEG测试和MRI扫描测量的大脑活动和结构的变化。我组织了一个国际财团，从7,000名个体（1,500名患者，2,500名亲属和3,000名对照）中获得DNA样本和生物标志物数据。美国？精神分裂症遗传学联盟一个可比较的独立研究，提供了一个复制的机会。这个样本的全基因组扫描几乎完成了，这将提供超过一百万个遗传标记，这是迄今为止最大和最全面的精神疾病遗传研究。我目前在我的博士后奖学金（卫生部）的最后一年，我现在寻求MRC的支持，继续领导这个非常有价值的样本的分析，并建立自己作为一个独立的研究人员在这个过程中。这项研究如何帮助阐明精神病的易感基因以及这些基因传递疾病风险的机制将促进对精神病的理解和治疗。

GENETICS OF PSYCHOSIS AT PRESENTPsychotic disorders affect 2% of the population and are within the seven leading causes of disability (WHO). Although psychotic disorders run in families and neuregulin 1 and dysbindin are promising candidate genes, unambiguous risk genes remain elusive. Genome-wide association allows testing hundreds of thousands of markers across the entire human genome in large samples and has successfully led to the identification of nearly 200 genes in 70 common illnesses like diabetes and heart disease. However, psychiatric diagnoses do not constitute easy traits for genetic research and I propose using biomarkers as an alternative. These biomarkers are quantitative biological traits characterising psychosis which are obtained by laboratory-based methods. AIMS OF THIS PROJECTTo use a genome-wide scan to examine the association between genetic variation and (iii) psychosis (in a conventional case-control design)(iv) biological markers of brain function or structure that are characteristic of the disease. WHAT WE PROPOSE TO DOFrom twin and family studies I selected the most suitable psychosis biomarkers. These include deficits in memory and other cognitive abilities as well as changes in brain activity and structure measured by EEG tests and MRI scans. I organised an international consortium to obtain DNA samples and biomarker data from 7,000 individuals [1,500 patients, 2,500 relatives and 3,000 controls]. The USA ?Consortium On the Genetics of Schizophrenia?, a comparable independent study, provides an opportunity for replications. A genome-wide scan of this sample is almost complete and this will provide more than one million genetic markers in what is the largest and most comprehensive genetic study of a psychiatric disease to date. I am currently in my final year of my post-doctoral fellowship (Department of Health) and I now seek support from the MRC to continue to lead the analysis of this highly valuable sample and to establish myself as an independent researcher in the process. HOW THIS RESEARCH COULD HELPElucidation of susceptibility genes for psychosis and the mechanisms by which these genes convey risk for the disease will advance the understanding and treatment of psychosis.