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: 8548402
• 负责人: Hader A. Mansour
• 金额: $ 45.66万
• 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/8548402
• 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 sequencing; novel; public health relevance; repository; response; risk variant; 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.

描述（由申请人提供）：精神分裂症（SZ）是一种常见的终身致残性疾病。世界各地对它的治疗仍然不令人满意。因此，对其病因和发病机制的研究是迫切需要的。基于大量的遗传力（~70%），基因定位工作正在进行中。已经发现了可信的风险变异，但确定的因素只能解释估计遗传力的一小部分。即使是有限的信息 强调了SZ发生的新途径，因此需要进行额外的基因定位研究。这些努力将需要成千上万的远系繁殖群体参与。我们的计划与近亲繁殖的人口承诺新的见解与更温和的努力。我们将建立在匹兹堡大学（PITT）和曼苏拉大学（MU，埃及）研究人员之间的合作R21项目。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患者的血缘关系增加。结果与SZ的隐性遗传危险因素一致。我们将采用一种名为血统纯合性（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和遗传上更复杂的疾病，如自闭症和智力残疾。我们的初步研究表明，深圳也取得了类似的成功。我们的建议也是新颖的，因为大多数SZ基因定位研究已经在高加索血统的参与者中进行。对其他族裔群体的调查，特别是那些具有不寻常遗传模式的群体的调查，可能会产生有用的、互补的见解。通过NIMH遗传学知识库，我们将与科学界的成员分享样本和数据，进一步增加我们工作的影响力。人们对利用基因组学研究的兴趣越来越大，也越来越认识到中东地区血缘关系对公共卫生的重要性。因此，我们培训并协助埃及同事在毛里求斯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，我们成功地利用我们的研究作为研究基础设施和能力建设的工具在MU。我们的目标是通过实施最先进的基因分析（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门知识将促进对其他疾病的研究。