Molecular Genetic Studies of Schizophrenia

精神分裂症的分子遗传学研究

• 批准号: MR/P005748/1
• 负责人: Michael Owen
• 金额: $ 306.71万
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP005748%2F1
• 关键词: Molecular; Genetic; Studies; Schizophrenia

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.

精神分裂症(SZ)是一种严重的精神障碍。治疗通常只有部分有效，或者根本没有效果，患有SZ的人在成年后的大部分时间里可能会严重残疾。开发更好的治疗SZ的方法是现代医学面临的最重要的挑战之一，但由于缺乏对导致SZ疾病的一系列生物过程的详细了解，我们应对和克服这一挑战的能力受到阻碍。它还受到缺乏客观测试的阻碍，无法做出诊断或将患者分类为可能从不同治疗中受益的亚组。我们的目标是使用现代遗传工具来解决这些差距。我们知道，基因在决定人们患上SZ的可能性方面很重要，而且涉及到许多基因。近年来，我们已经确定了导致风险的特定基因和突变，在这样做的过程中，我们对一些一般的疾病机制有了深入的了解。SZ的大部分风险尚未与特定的DNA变异有关，但我们的发现表明，调节大脑中神经元相互通信的蛋白质存在异常，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的基因和机制经常与影响其他精神和大脑发育障碍的基因重叠，包括双相情感障碍、自闭症和智力残疾。有明确的证据表明，基因对SZ的贡献包括相当常见的DNA变异(风险等位基因)，但每一种都只会轻微增加风险；其中许多现在已经被识别出来。它还包括罕见但会导致疾病风险极大增加的等位基因；这些等位基因中被识别的较少。在目前的提案中，我们的方法是将新的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。稀有的等位基因在提示致病和保护机制方面可能特别有用。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，我们的研究将为改变对其他疾病的理解的机制研究提供亟需的资源，例如癌症。我们实验室的重点是罕见的突变，但我们也会将这些发现与我们参与的常见变异的遗传学研究结果结合起来，以更全面地了解SZ的原因。我们将使用这些数据来识别倾向于丰富风险等位基因的广泛生物过程，然后从那些包含疾病遗传信号的更具体的致病子过程中分离出来。这种方法已经在我们之前识别的中等数量的风险等位基因上取得了成功。我们相信，通过这样做，我们可以为理解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识别SZ内和SZ之间的特定患者群体以及相关疾病，在这些疾病中，成员在特定生物过程中具有丰富的风险等位基因。这里的成功将开始允许精神病学中第一个生物学有效的分类，从而解决其他主要知识空白之一，并导致精神病学临床和介入研究的改善。我们相信，这些目标的完成将带来对SZ基础生物学的洞察，将提供治疗的新靶点，影响临床诊断，并将提供资源和试剂(以因果和保护性突变、致病途径和关于有效患者分组的信息的形式)，将设定下一个十年精神病学的基础和临床翻译议程。

项目成果

Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia.

• DOI: 10.1186/s13229-017-0137-9
• 发表时间: 2017
• 期刊: Molecular autism
• 影响因子: 6.2
• 作者: Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium

Association Between Schizophrenia-Related Polygenic Liability and the Occurrence and Level of Mood-Incongruent Psychotic Symptoms in Bipolar Disorder.

• DOI: 10.1001/jamapsychiatry.2017.3485
• 发表时间: 2018-01-01
• 期刊: JAMA psychiatry
• 影响因子: 25.8
• 作者: Allardyce J;Leonenko G;Hamshere M;Pardiñas AF;Forty L;Knott S;Gordon-Smith K;Porteous DJ;Haywood C;Di Florio A;Jones L;McIntosh AM;Owen MJ;Holmans P;Walters JTR;Craddock N;Jones I;O'Donovan MC;Escott-Price V
• 通讯作者: Escott-Price V

Rare Genome-Wide Copy Number Variation and Expression of Schizophrenia in 22q11.2 Deletion Syndrome.

• DOI: 10.1176/appi.ajp.2017.16121417
• 发表时间: 2017-11-01
• 期刊: The American journal of psychiatry
• 作者: Bassett AS;Lowther C;Merico D;Costain G;Chow EWC;van Amelsvoort T;McDonald-McGinn D;Gur RE;Swillen A;Van den Bree M;Murphy K;Gothelf D;Bearden CE;Eliez S;Kates W;Philip N;Sashi V;Campbell L;Vorstman J;Cubells J;Repetto GM;Simon T;Boot E;Heung T;Evers R;Vingerhoets C;van Duin E;Zackai E;Vergaelen E;Devriendt K;Vermeesch JR;Owen M;Murphy C;Michaelovosky E;Kushan L;Schneider M;Fremont W;Busa T;Hooper S;McCabe K;Duijff S;Isaev K;Pellecchia G;Wei J;Gazzellone MJ;Scherer SW;Emanuel BS;Guo T;Morrow BE;Marshall CR;International 22q11.2DS Brain and Behavior Consortium
• 通讯作者: International 22q11.2DS Brain and Behavior Consortium

Are Alzheimer's and coronary artery diseases genetically related to longevity?

• DOI: 10.3389/fpsyt.2022.1102347
• 发表时间: 2022
• 期刊: FRONTIERS IN PSYCHIATRY
• 影响因子: 4.7
• 作者: Bellou, Eftychia;Escott-Price, Valentina
• 通讯作者: Escott-Price, Valentina

Genome-wide association study reveals greater polygenic loading for schizophrenia in cases with a family history of illness.

• DOI: 10.1002/ajmg.b.32402
• 发表时间: 2016-03
• 期刊: American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics
• 作者: Bigdeli TB;Ripke S;Bacanu SA;Lee SH;Wray NR;Gejman PV;Rietschel M;Cichon S;St Clair D;Corvin A;Kirov G;McQuillin A;Gurling H;Rujescu D;Andreassen OA;Werge T;Blackwood DH;Pato CN;Pato MT;Malhotra AK;O'Donovan MC;Kendler KS;Fanous AH;Schizophrenia Working Group of the Psychiatric Genomics Consortium
• 通讯作者: Schizophrenia Working Group of the Psychiatric Genomics Consortium