1/3 - Genomics of Schizophrenia in the South Africa Xhosa

描述（由申请人提供）：这个国际合作项目的目标是确定南非科萨人中精神分裂症的基因。三个参与研究中心是哥伦比亚大学，纽约（Ezra Susser，PI），华盛顿大学，西雅图（玛丽-克莱尔金，杰克麦克莱伦，汤姆沃尔什，MPI）和南非开普敦大学（丹斯坦，PI）。精神分裂症的绝大多数遗传基础尚未得到解释。我们假设，精神分裂症的重要基因和途径将在不同的受影响个体中隐藏不同的，严重的致病突变。考虑到非洲人群的遗传多样性，我们希望找到尚未从其他人群研究中发现的精神分裂症基因。该项目还将促进非洲神经精神疾病基因发现研究的发展。在1100名患有精神分裂症的科萨人和1100名年龄和性别匹配的科萨对照中，我们将比较外显子组、侧翼调控位点和非编码RNA（通过外显子组测序获得）的图谱以及结构基因组变体（通过arrayCGH获得）的图谱。将鉴定和评估罕见/私人变异和古非洲等位基因。与对照相比，精神分裂症个体中富集有害突变的基因将被定义为候选基因。将在NIMH序列数据库中评估候选基因的变异谱，这些数据库来自其他人群的精神分裂症研究。该项目将是第一个使用现代基因组测序方法研究撒哈拉以南非洲血统人群中的精神分裂症的项目。如果成功，我们的方法将在全球人群中识别出对这种疾病重要的基因。这些基因将刺激未来的努力，以开发更有效的治疗和预防策略。

DESCRIPTION (provided by applicant): The goal of this international collaborative project is to identify genes responsible for schizophrenia in the Xhosa population of South Africa. The three participating sites are Columbia University, New York (Ezra Susser, PI), University of Washington, Seattle (Mary- Claire King, Jack McClellan, Tom Walsh, MPIs), and University of Cape Town, South Africa (Dan Stein, PI). The vast majority of the genetic basis for schizophrenia has yet to be explained. We hypothesize that genes and pathways important to schizophrenia will harbor different, severe disease-causing mutations in different affected individuals. Given the genetic diversity of African populations, we expect to find genes for schizophrenia that have not yet emerged from studies of other populations. This project will also foster the development of gene discovery research for neuropsychiatric disorders in Africa. In 1100 Xhosa individuals with schizophrenia and 1100 age and gender-matched Xhosa controls, we will compare profiles of exomes, flanking regulatory sites, and noncoding RNAs (obtained by exome sequencing) and profiles of structural genomic variants (obtained by arrayCGH). Both rare/private variants and ancient African alleles will be identified and evaluated. Genes enriched for deleterious mutations in individuals with schizophrenia compared to controls will be defined as candidates. Variant profiles of candidate genes will be assessed in NIMH sequence databases derived from schizophrenia studies of other populations. This project will be the first to use modern genomic sequencing approaches to study schizophrenia in a population of sub-Saharan African lineage. If successful, our approach will identify genes important for the disorder in populations worldwide. These genes will stimulate future efforts to develop more effective treatment and prevention strategies.