Multi-pronged genetic studies of schizophrenia in an inbred population

描述(申请人提供)：精神分裂症(SZ)是一种常见的终生致残性障碍。它的治疗在世界各地仍然不令人满意。因此，迫切需要对其病因和发病机制进行研究。基于相当大的遗传力(~70%)，基因图谱的工作正在进行中。已经发现了可信的风险变量，但已确定的因素只解释了估计的遗传力的一小部分。即使是有限的信息 强调了SZ发生的新途径，因此有必要进行额外的基因图谱研究。这样的努力将需要数以千计的远亲群体的参与者。我们的近亲繁殖人口计划承诺以更少的努力获得新的见解。我们将在匹兹堡大学(匹兹堡)和曼苏拉大学(埃及MU)研究人员之间的合作R21项目的基础上再接再厉。在尼罗河三角洲地区，我们发现与未受影响的对照组相比，SZ患者之间的血缘关系增加。这一结果与SZ的隐性遗传危险因素相一致。我们将使用一种名为按血统纯合(HBD)分析的强大工具，该工具已成功用于绘制数百种隐性孟德尔疾病以及自闭症和智力残疾等更复杂的遗传疾病的图谱。我们的初步研究表明，深圳也取得了类似的成功。我们的建议是新颖的，因为大多数SZ基因图谱研究都是在高加索血统参与者中进行的。对其他种族群体的调查，特别是那些具有不寻常遗传模式的群体，可能会产生有用的、互补的见解。通过NIMH基因库，我们将与科学界成员共享样本和数据，进一步增加我们工作的影响。人们对利用基因组学研究以及认识到中东血缘关系的公共卫生相关性越来越感兴趣。因此，我们培训和协助我们的埃及同事在慕尼黑大学建立了一个遗传学研究小组，包括一个分子遗传学实验室。我们已经发表了我们的工作，并获得了其他资金来开始进一步的研究。因此，我们成功地将我们的研究作为墨尔本大学研究基础设施和能力建设的载体。我们的目标是通过实施最先进的遗传分析，包括计算机和生物信息学，扩大密歇根大学的遗传学研究。通过这项工作获得的资源和专业知识将促进对其他疾病的研究。 公共卫生相关性：精神分裂症是一种常见的、严重的、世界范围的疾病，目前治疗不足。这种疾病的起源尚不清楚。了解精神分裂症的根本原因将有助于我们了解这种毁灭性疾病的根源，也可以帮助我们设计更有效的药物。我们的研究将集中在埃及精神分裂症的遗传风险因素上。我们的研究将受益于Locl社区的结构，包括大型合作家庭。它们将促进当地的研究基础设施和能力建设工作，并将补充美国正在进行的工作。因此，我们的研究不仅与埃及人相关，也与美国公民相关。

DESCRIPTION (provided by applicant): Schizophrenia (SZ) is a common, lifelong, disabling disorder. Its treatment remains unsatisfactory across the world. Thus, research into its causation and pathogenesis is needed urgently. Based on the substantial heritability (~70%), gene mapping efforts are in progress. Credible risk variants have been found, but the identified factors explain only a small proportion of the estimated heritability. Even the limited information has highlighted novel pathways for SZ genesis, so additional gene mapping studies are warranted. Such efforts will require many thousands of participants in outbred populations. Our plan with an inbred population promises novel insights with more modest effort. We will build on a collaborative R21 project between investigators at the University of Pittsburgh (PITT) and Mansoura University (MU, Egypt). In the Nile delta region, we have found increased consanguinity among patients with SZ compared with unaffected controls. The results are consistent with recessive genetic risk factors for SZ. We will employ a powerful tool called homozygosity by descent (HBD) analysis that has been successfully used to map several hundred recessive Mendelian diseases and genetically more complex disorders like autism and intellectual disability. Our preliminary studies suggest similar success for SZ. Our proposal is novel also because most SZ gene mapping studies have been conducted among Caucasian ancestry participants. Investigations of other ethnic groups, particularly those with unusual patterns of inheritance may yield useful, complementary insights. Through the NIMH genetics repository, we will share samples and data with members of the scientific community, further increasing the impact of our work. There is increasing interest in harnessing genomics research, as well as recognition of the public health relevance of consanguinity in the Middle East. Accordingly, we have trained and assisted our Egyptian colleagues to establish a genetics research group at MU, including a molecular genetics laboratory. We have published our work and obtained other funds to start additional research. Thus, we have successfully used our research as a vehicle for research infrastructure and capacity building at MU. Our goal is to scale up the genetics research at MU by implementing state of the art genetic analyses, including computing and bioinformatics. The resources and expertise garnered through this work will facilitate research into other diseases. PUBLIC HEALTH RELEVANCE: Schizophrenia is a common, severe, world-wide disorder for which treatment is presently inadequate. The origins of this disorder are unknown. Knowledge about the root causes of schizophrenia will help us to understand the origins of this devastating disorder and could also help us to design more effective medicines. Our studies will focus on genetic risk factors for schizophrenia in Egypt. Our studies will benefit from the structure of locl communities, including large, cooperative families. They will enable local research infrastructure and capacity building work and will complement ongoing work in the USA. Thus our studies are relevant not only for Egyptians, but also for US citizens.