A Genetic Study of Schizophrenia Endophenotypes in Sub-Saharan Africans

撒哈拉以南非洲人精神分裂症内表型的遗传学研究

• 批准号: 8074239
• 负责人: IKWUNGA WONODI
• 金额: $ 15万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-16 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8074239
• 关键词: Admixture; African; African American; American; Architecture; Baltimore; Behavioral Symptoms; Biological Markers; Biomedical Research; Certification; Chromosome Mapping; Clinical; Cognition; Country; DNA; Data; Development; Disease; Ethics Committees; European; Eye Movements; Family; Future; Genes; Genetic; Genetic Polymorphism; Genome; Genotype; Geographic Locations; Goals; Guidelines; Heritability; Hospitals; Impairment; Income; Incubators; Individual; Institutional Review Boards; International; Interview; Laboratories; Link; Linkage Disequilibrium; Maps; Maryland; Measurement; Measures; Memory impairment; Mental Health; Mentors; Mission; Molecular; Neurobiology; Neurons; Nigeria; Older Population; Pathway interactions; Pharmacology; Phenotype; Population; Prevalence; Proteins; Protocols documentation; Reporting; Research; Research Infrastructure; Research Personnel; Sampling; Schizophrenia; Short-Term Memory; Site; Smooth Pursuit; Structure; Susceptibility Gene; Syndrome; System; Testing; Training; Translating; United States National Institutes of Health; Universities; Variant; base; clinical Diagnosis; cohort; disorder risk; endophenotype; functional disability; functional outcomes; genetic analysis; human subject; infrastructure development; insight; interest; international center; multidisciplinary; neuropsychiatry; novel; oculomotor; predictive pursuit; research and development; response; synaptic function; trait

DESCRIPTION (provided by applicant): Schizophrenia (SZ) is a debilitating neuropsychiatric disease with a prevalence of ~1% across diverse cultures and geographic areas. The clinical syndrome likely represents a heterogeneous group of diseases and etiologic paths. Despite evidence of a substantial genetic component, findings from traditional genetic studies have been inconsistent and difficult to replicate [1;2;3;4] seriously hindering progress in the field. An alternative approach is to simplify the problem by using quantifiable neurobiological traits that are reproducible and have increased genetic component. Such traits may mark specific aspects of disease risk that delineate more specific molecular pathways linking susceptibility genes (of small effect) to translated protein or function compared to analysis of behavioral symptoms only [5]. One highly reproducible SZ biomarker (i.e., endophenotype) is the smooth pursuit eye movement abnormality (SPEM, also called eyetracking). The demonstration of SPEM abnormality in SZ has been replicated in over 50 studies with few negative reports [6]. We have shown that the predictive pursuit eyetracking subcomponent of SPEM has a higher heritability (i.e., genetic contribution) than traditional SPEM measures [7;8;9;10]. Notably, we have used predictive pursuit to parse differences in small gene effects between SZ and healthy controls that would otherwise have gone unnoticed using the traditional SPEM measure or clinical diagnosis [11;12]. Studies suggest that predictive pursuit is conceptually similar to working memory (WM) [13;14;15]. WM impairments have emerged as critical predictors of the poor functional outcome and disability observed in SZ [16;17;18]. Thus, identifying the molecular mechanisms underlying predictive pursuit impairment could facilitate the discovery of novel targets for the development of rational pharmacology for cognition enhancement in SZ. Our preliminary results suggest a significant effect of neurexin 3 gene (NRXN3; encodes a family of neuronal proteins essential for synaptic function) [19] variants on predictive pursuit and WM impairments in African-American (AA), but not European-American (EA) SZ individuals, and point to loci-of-interest for more extensive molecular characterization and gene mapping. We have begun fine mapping efforts, but there is an admixture problem. This prompted the need for a homogenous sub-Saharan African sample of Ibos in Nigeria. The African sample will also be useful for other endophenotype-based gene mapping efforts, beyond NRXN3. The goal of the proposed R21 is to build research capacity at the Neuropsychiatric Hospital Rumuigbo, Port Harcourt to generate pilot data in Ibos for a subsequent R01 in a deeply phenotyped sample. The advantages of the Nigerian site include, small linkage disequilibrium (LD) blocks ideal for gene mapping in an old population (similar to the Yoruba in the International HapMap Genome Project), with no admixture problems, and responding to the NIH Fogarty International Center's mission to "to support capacity-building, research infrastructure development, and research mentoring in order to develop a multidisciplinary mental health research workforce in low- and middle-income countries". PUBLIC HEALTH RELEVANCE: This collaborative project between U.S and Nigerian investigators will build capacity for biomedical research at the Nigerian site. It will characterize schizophrenia endophenotypes (or liability markers) in an endogenous sub-Saharan African cohort of Igbo and test the feasibility of performing endophenotype-based genetic studies in this homogenous old population. Findings would provide important insights for future genetic studies, including gene mapping in a population with smaller LD blocks and different genetic architecture.

描述(申请人提供)：精神分裂症(SZ)是一种使人衰弱的神经精神疾病，在不同的文化和地理区域中患病率约为1%。临床综合征可能代表了一组不同的疾病和病因路径。尽管有大量的基因成分的证据，但传统基因研究的结果并不一致，很难复制[1；2；3；4]，这严重阻碍了该领域的进展。另一种方法是通过使用可量化的神经生物学特征来简化问题，这些特征是可复制的，并具有更多的遗传成分。与仅分析行为症状相比，这些特征可能标志着疾病风险的特定方面，描绘了将易感基因(小影响)与翻译的蛋白质或功能联系起来的更具体的分子路径[5]。SZ的一个高重复性生物标志物(即内表型)是平滑追踪眼动异常(SPEM，也称为眼球跟踪)。SZ的SPEM异常的证明已经在50多项研究中重复，几乎没有负面报道[6]。我们已经证明，与传统的SPEM测量方法相比，SPEM的预测性追求刺眼亚组分具有更高的遗传度(即遗传贡献)[7；8；9；10]。值得注意的是，我们使用预测性追踪来分析SZ和健康对照之间小基因效应的差异，否则使用传统的SPEM测量或临床诊断就不会注意到这些差异[11；12]。研究表明，预测性追求在概念上类似于工作记忆[13；14；15]。WM损伤已成为SZ观察到的不良功能结局和残疾的关键预测因子[16；17；18]。因此，识别预测性追踪损害的分子机制有助于发现新的靶点，为开发合理的药物来提高深圳地区的认知能力提供帮助。我们的初步结果表明，在非裔美国人(AA)而不是欧洲裔美国人(EA)SZ患者中，neuresin 3基因(NRXN3；编码一系列突触功能必需的神经元蛋白)[19]变体对预测性追踪和WM损伤有显著影响，并指出了更广泛的分子特征和基因定位的兴趣位点。我们已经开始了精细的测绘工作，但存在一个混合问题。这促使尼日利亚需要一个同质的撒哈拉以南非洲IBOs样本。除NRXN3外，非洲样本还将用于其他基于内表型的基因作图工作。拟议的R21的目标是在哈科特港的Rumuigbo神经精神病院建立研究能力，以便在IBOS中为随后的R01产生深度表型样本的试点数据。尼日利亚网站的优势包括，非常适合在老年人口中绘制基因图谱的小连锁不平衡(LD)块(类似于国际HapMap基因组计划中的约鲁巴人)，没有混合问题，并响应了NIH Fogarty国际中心的使命，即“支持能力建设、研究基础设施发展和研究指导，以便在低收入和中等收入国家发展一支多学科的精神卫生研究队伍”。 公共卫生相关性：美国和尼日利亚调查人员之间的这一合作项目将在尼日利亚现场建设生物医学研究能力。它将表征内源性撒哈拉以南非洲Igbo人群中精神分裂症的内表型(或易感标记)，并测试在这一同质老年人群中进行基于内表型的遗传研究的可行性。这些发现将为未来的遗传学研究提供重要的见解，包括在具有较小LD区块和不同遗传结构的种群中进行基因图谱绘制。