Molecular Genetic Studies of Schizophrenia

精神分裂症（SZ）是一种严重的精神疾病。治疗通常只有部分效果，或者根本没有效果，患有SZ的人可能在成年后的大部分时间里都处于严重残疾状态。为SZ开发更好的治疗方法是现代医学面临的最重要的挑战之一，但由于缺乏导致该疾病的生物过程的详细知识，我们应对和克服这一挑战的能力受到阻碍。缺乏客观的测试来进行诊断或将患者分为可能受益于不同治疗的亚组，也阻碍了这一工作。我们的目标是利用现代遗传工具来解决这些差距。我们知道基因在决定人们患SZ的可能性方面很重要，而且很多基因都参与其中。近年来，我们已经确定了导致风险的特定基因和突变，在此过程中，我们正在深入了解一些一般的疾病机制。SZ的大部分风险尚未与特定的DNA变异联系起来，但我们的发现指向了调节大脑中神经元如何相互交流的蛋白质的异常，这些蛋白质对记忆和学习至关重要。研究结果还表明，影响SZ的基因及其机制经常与影响其他精神和大脑发育障碍（包括双相情感障碍、自闭症和智力残疾）的基因重叠。有明确的证据表明，对SZ的遗传贡献包括相当常见的DNA变异（风险等位基因），但每个变异只略微增加风险；其中许多现在已经被确认。它还包括罕见的等位基因，但会大大增加紊乱的风险；其中被确认的更少。我们目前的建议是将新的DNA测序技术应用于我们非常大的样本，旨在识别具有大影响的罕见风险等位基因。罕见等位基因在提示致病和保护机制方面可提供特别的信息。此外，对疾病有重大影响的罕见突变的影响可以在细胞或动物中有效地模拟；因此，我们的研究将为机制研究提供急需的资源，这些研究已经改变了对其他疾病（例如癌症）的理解。我们实验室的重点是罕见突变，但我们也会将这些发现与我们参与的常见变异的遗传研究结果结合起来，以获得更全面的SZ病因图。我们将利用这些数据来确定风险等位基因丰富的广泛生物过程，然后从包含该疾病遗传信号的更具体的致病亚过程中分离出来。这种方法在我们之前确定的中等数量的风险等位基因上已经取得了成功。我们相信，这样做可以为理解SZ背后的基本生物学机制做出重大贡献。我们还将利用这些发现来调查是否可以确定SZ内和跨SZ的特定患者群体以及相关疾病，其中成员在特定生物学过程中具有丰富的风险等位基因。这里的成功将开始允许第一个生物学上有效的精神病学分类，从而解决其他主要的知识空白之一，并导致精神病学临床和介入研究的改进。我们相信，这些目标的完成将为SZ的基础生物学提供新的见解，将为治疗提供新的靶点，影响临床诊断，并将提供资源和试剂（以因果和保护性突变，致病途径和有效患者分组的形式），这将为未来十年的精神病学奠定基础和临床转化议程。

Schizophrenia (SZ) is a severe psychiatric disorder. Treatments are often only partially effective, or not effective at all, and people with SZ can be profoundly disabled for most of their adult life. Developing better treatments for SZ is one of the most important challenges facing modern medicine but our ability to meet and overcome this challenge is hindered by a lack of detailed knowledge about the range of biological processes that cause the disorder. It is also obstructed by a lack of objective tests with which to make a diagnostis or classify patients into subgroups who might benefit from different treatments. We aim to use modern genetic tools to address these gaps. We know that genes are important in determining how likely people are to develop SZ, and that many genes are involved. In recent years, we have identified specific genes and mutations that contribute to risk, and in doing so, we are gaining insights into some general disease mechanisms. Most of the risk for SZ is not yet linked to specific DNA variants, but the findings we have made are pointing to abnormalities in proteins that regulate how neurones in the brain communicate with each other and are pivotal to memory and learning. The findings also show that the genes, and therefore the mechanisms, influencing SZ frequently overlap with those that influence other psychiatric and brain developmental disorders including bipolar disorder, autism, and intellectual disability. There is clear evidence that the genetic contribution to SZ includes DNA variants (risk alleles) that are fairly common but each only slightly increases risk; many of these have now been identified. It also includes alleles that are rare but confer very large increases in risk of disorder; fewer of these have been identified. Our approach in the current proposal is to apply the new DNA sequencing technology to our very large samples aiming to identify rare risk alleles of large effect. Rare alleles can be particularly informative for suggesting both disease causing and protective mechanisms. Moreover, the effects of rare mutations with big impacts on disease can be effectively modelled in cells or in animals; thus our study will provide much needed resources for the mechanistic studies that have transformed understanding of other disorders, for example cancer. Our laboratory focus is on rare mutations, but we will also integrate the findings with the results of the genetic studies of common variation we are involved in to gain a more comprehensive picture of the causes of SZ. We will use the data to identify broad biological processes that tend to be enriched for the risk alleles, and then isolate from those more specific pathogenic sub-processes that contain the genetic signals for the disorder. This sort of approach has already been successful with the moderate number of risk alleles we have previously identified. We believe that in doing so, we can make major contributions to understanding the fundamental biological mechanisms behind SZ. We will also use the findings to investigate if particular groups of patients within SZ and across SZ and related disorders can be identified in which members are enriched for risk alleles in particular biological processes. Success here will begin to allow the first biologically valid classifications in psychiatry, thus addressing one of the other major knowledge gaps and lead to improved clinical and interventional studies in psychiatry.We believe completion of these aims will deliver insights into the fundamental biology of SZ, will deliver novel targets for treatments, influence clinical diagnostics, and will provide the resources and reagents (in the form of causal and protective mutations, pathogenic pathways, and information about valid patient groupings) that will set the fundamental and clinical translational agenda in psychiatry for the next decade.