Multi-pronged genetic studies of schizophrenia in an inbred population

近交群体精神分裂症的多管齐下遗传学研究

• 批准号: 8410815
• 负责人: Hader A. Mansour
• 金额: $ 58.23万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-20 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8410815
• 关键词: Affect; Alleles; Arabs; Area; Autistic Disorder; Bioinformatics; Caucasians; Caucasoid Race; Chromosome Mapping; Clinical; Clinical Investigator; Communities; Complement; Complex; Computer software; Consanguinity; Consent; Consultations; Data; Disease; Egypt; Ethnic group; Etiology; Exhibits; Family; Funding; Genes; Genetic; Genetic Polymorphism; Genetic Research; Genetic Risk; Genomics; Genotype; Goals; Grant; Hereditary Disease; Heritability; Inbreeding; Individual; Inheritance Patterns; Institution; Intellectual functioning disability; Investigation; Knowledge; Laboratories; Lead; Maps; Medicine; Middle East; Molecular Genetics; Mutation; National Institute of Mental Health; Odds Ratio; Paper; Participant; Pathogenesis; Pathway interactions; Patients; Plant Roots; Population; Predisposition; Psychiatric Diagnosis; Public Health; Publishing; Publishing Peer Reviews; Relative (related person); Research; Research Infrastructure; Research Personnel; Research Project Grants; Resources; Risk; Sampling; Schizophrenia; Source; Structure; Testing; Training; United States National Institutes of Health; Universities; Variant; Work; base; cognitive function; design; follow-up; genetic analysis; genetic risk factor; improved; insight; interest; member; next generation; novel; public health relevance; repository; response; scale up; success; tool

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.

描述（由申请人提供）：精神分裂症（SZ）是一种常见的、终生的、致残的疾病。它的治疗在世界范围内仍然不能令人满意。因此，迫切需要对其因果关系和发病机制进行研究。基于显着的遗传力（~70%），基因图谱工作正在进行中。已经发现了可信的风险变异，但已确定的因素仅解释了估计遗传力的一小部分。即使信息有限 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千名近亲繁殖群体的参与者。我们针对近交种群的计划有望通过更适度的努力获得新颖的见解。我们将以匹兹堡大学 (PITT) 和曼苏拉大学（埃及 MU）的研究人员之间的 R21 合作项目为基础。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 患者的近亲关系有所增加。结果与 SZ 的隐性遗传危险因素一致。我们将采用一种强大的工具，称为血统纯合性（HBD）分析，该工具已成功用于绘制数百种隐性孟德尔疾病和遗传上更复杂的疾病（如自闭症和智力障碍）。我们的初步研究表明深圳也取得了类似的成功。我们的提议很新颖，因为大多数 SZ 基因图谱研究都是在白人血统参与者中进行的。对其他种族群体的研究，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、补充性的见解。通过 NIMH 遗传学存储库，我们将与科学界成员共享样本和数据，进一步提高我们工作的影响力。人们对利用基因组学研究越来越感兴趣，并且认识到中东地区血缘关系的公共卫生相关性。因此，我们培训并协助我们的埃及同事在密苏里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更多的研究。因此，我们成功地将我们的研究用作密苏里大学研究基础设施和能力建设的工具。我们的目标是通过实施最先进的遗传分析（包括计算和生物信息学）来扩大密苏里大学的遗传学研究规模。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、世界性的疾病，目前治疗方法还不够。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破坏性疾病的起源，也可以帮助我们设计出更有效的药物。我们的研究将重点关注埃及精神分裂症的遗传风险因素。我们的研究将受益于当地社区的结构，包括大型的合作家庭。它们将支持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。