Multi-pronged genetic studies of schizophrenia in an inbred population

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。我们的近亲繁殖人口计划有望通过更温和的努力获得新的见解。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越来越感兴趣，

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