A Genetic Study of Schizophrenia Endophenotypes in Sub-Saharan Africans

描述（由申请人提供）：精神分裂症（SZ）是一种使人衰弱的神经精神疾病，在不同文化和地理区域的患病率约为1%。临床综合征可能代表一组异质性疾病和病因学途径。尽管有大量的遗传成分的证据，从传统的遗传研究的结果一直是不一致的，难以复制[1;2;3;4]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，这些特征是可重复的，并且具有增加的遗传成分。这些特征可能标志着疾病风险的特定方面，与仅分析行为症状相比，这些特征描绘了将易感基因（影响较小）与翻译的蛋白质或功能联系起来的更具体的分子途径[5]。一种高度可再现的SZ生物标志物（即，内表型）是平滑追踪眼球运动异常（SPEM，也称为眼动追踪）。SZ中SPEM异常的证明已在50多项研究中重复，很少有阴性报告[6]。我们已经表明，SPEM的预测追踪眼动子成分具有更高的遗传性（即，遗传贡献）比传统的SPEM措施[7;8;9;10]。值得注意的是，我们已经使用预测追踪来解析SZ和健康对照之间的小基因效应的差异，否则使用传统的SPEM测量或临床诊断会注意不到这些差异[11;12]。研究表明，预测追踪在概念上类似于工作记忆（WM）[13;14;15]。WM损伤已成为SZ中观察到的不良功能结局和残疾的关键预测因素[16;17;18]。因此，确定潜在的预测追求损害的分子机制，可以促进发现新的目标，为发展合理的药理学，提高在SZ的认知。我们的初步结果表明，neurexin 3基因（NRXN 3;编码突触功能所必需的神经元蛋白家族）[19]变体对非裔美国人（AA）而不是欧美人（EA）SZ个体的预测追踪和WM损伤有显著影响，并指出了更广泛的分子表征和基因定位的兴趣位点。我们已经开始了精细的绘图工作，但存在一个混合问题。这促使人们需要在尼日利亚建立一个同质的撒哈拉以南非洲伊博人样本。非洲样本也将有助于其他基于内表型的基因作图工作，除了NRXN 3。拟议的R21的目标是在哈科特港的神经精神病医院Rumuigbo建立研究能力，以在Ibos中生成试验数据，用于随后的R 01中的深度表型样本。尼日利亚站点的优点包括，小连锁不平衡（LD）块理想的基因定位在一个老的人口（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NIH Fogarty国际中心的使命“支持能力建设，研究基础设施的发展，和研究指导，以便在低收入和中等收入国家培养一支多学科的心理健康研究队伍”。 公共卫生相关性：美国和尼日利亚研究人员之间的这一合作项目将在尼日利亚基地建立生物医学研究能力。它将描述精神分裂症内在表型（或责任标志物）在一个内源性撒哈拉以南非洲队列的伊博和测试的可行性进行内在表型为基础的遗传研究，在这个同质的老年人口。研究结果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块和不同遗传结构的人群中进行基因定位。

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.