A Genetic Study of Schizophrenia Endophenotypes in Sub-Saharan Africans

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了异质组的疾病和病因途径。尽管有证据表明存在大量遗传成分，但传统遗传研究的结果不一致且难以复制[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，并且增加了遗传成分。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（影响小）与翻译蛋白或功能联系起来的更具体的分子途径。一个高度可重复的SZ生物标志物（即内表型）是平滑追求眼动异常（SPEM，也称为眼动追踪）。SZ的SPEM异常已经在50多个研究中得到证实，但很少有负面报道[1]。我们已经证明SPEM的预测追踪眼动子成分比传统的SPEM测量具有更高的遗传力（即遗传贡献）[7;8;9;10]。值得注意的是，我们已经使用预测追踪来分析SZ和健康对照之间小基因效应的差异，否则使用传统的SPEM测量或临床诊断就会被忽视[11；12]。研究表明，预测性追求在概念上与工作记忆（WM）相似[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素[16;17;18]。因此，确定预测性追求障碍的分子机制有助于发现新的靶点，开发合理的药理学来增强SZ的认知能力。我们的初步结果表明，neurexin 3基因（NRXN3；编码突触功能必需的神经元蛋白家族）[19]变异对非裔美国人（AA）的预测性追求和WM损伤有显著影响，但对欧裔美国人（EA） SZ个体没有影响，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，但是有一个混合问题。这促使人们需要在尼日利亚对撒哈拉以南非洲的伊博人进行同质取样。除了NRXN3之外，非洲样本也将对其他基于内表型的基因定位工作有用。拟议的R21的目标是在哈科特港鲁穆伊博神经精神病医院建立研究能力，以便在Ibos中产生试点数据，用于随后在深度表型样本中进行R01。尼日利亚站点的优势包括：小的连锁不平衡（LD）块非常适合在老年人口中进行基因定位（类似于国际HapMap基因组计划中的约鲁巴人），没有混杂问题，并且响应了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多学科的精神卫生研究队伍”。

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.