Gene Networks Influencing Psychotic Dysconnectivity in African Americans

描述（由申请人提供）：异常的结构和功能连接（大脑区域之间的相互作用）是精神分裂症和精神病性双相情感障碍等精神病的病理生理学的核心。现代神经影像学技术和分析策略提供了前所未有的能力，更充分地表征功能和结构的精神病性分离。患有精神病的个体及其未受影响的亲属具有异常连接，这表明至少一部分精神病性断开与疾病的遗传易感性有关。基于成像的连接性内表型非常适合于辅助推定风险基因的功能表征，使我们能够超越基因型-表型关联，以描绘引起精神病的机制。最近，欧洲血统个体的大规模外显子组测序为增加精神病风险的特定遗传变异提供了迄今为止最有力的证据。这些主要罕见的突变分布在涉及神经元过程的基因网络中，包括钙通道和突触后信号传导。我们的目标是在不同的种族群体中复制这些有希望的基因发现， 非裔美国人，并确定这些基因集是否以及如何影响精神病的断开。非裔美国人，一个服务不足的人群，在这些网络中比欧洲血统的个体多32%的高度有害的非同义罕见变异，提高了我们检测罕见变异的能力。我们的目标是：（1）使用基于人类连接组计划的现代MRI采集和分析技术，记录750名非裔美国人（375名精神病患者和375名人口统计学匹配的对照受试者）的精神病性连接断开。我们将检验以下假设，即精神病的诊断和维度指数与减少的全局功能连接性但完整的全局结构连接性相关联，并结合特定区域或区域之间的异常连接性;（2）进行全外显子组测序（WES），以使用网络中心分析策略来测试来自先前鉴定的基因集中的基因的罕见非同义变体对精神病风险的影响。我们将检验电压门控钙离子通道、ARC相关支架蛋白和NMDAR突触后信号复合物影响精神病的诊断和维度指标的假设;（3）应用同样的网络中心检验来确定与疾病风险有关的基因组是否也影响功能性神经元损伤。 和结构性精神分裂将这些遗传途径与精神病性分离联系起来，将为基因组对精神病的影响提供机制性的见解。 我们的合作应用程序包括耶鲁/哈特福德医院（DC Glahn PI），斯坦福大学（RA Poldrack PI）和德克萨斯州生物医学研究所（J Blangero PI）的网站。我们的研究结果应该加强我们对精神病遗传结构的理解，并为穿越已识别的遗传网络和行为定义的疾病之间的鸿沟提供重要线索。

DESCRIPTION (provided by applicant): Abnormal structural and functional connectivity (interaction between brain regions) is central to the pathophysiology of psychotic illnesses like schizophrenia and psychotic bipolar disorder. Modern neuroimaging techniques and analytic strategies provide an unprecedented capacity to more fully characterize the functional and structural psychotic disconnectivity. Individuals with psychotic illness and their unaffected relatives have abnormal connectivity, suggesting that at least a portion of psychotic disconnectivity is associated with genetic predisposition for the diseases. Imaging-based connectivity endophenotypes are ideally suited to aid the functional characterization of putative risk genes, allowing us to move beyond a genotype-phenotype association to delineating mechanisms that give rise to psychotic illnesses. Recently, large-scale exome sequencing in individuals of European ancestry provided the strongest evidence to date for specific genetic variants that increase risk for psychosis. These primarily rare mutations were spread across gene networks involved in neuronal processes, including calcium channels and postsynaptic signaling. Our goals are to replicate these promising genetic findings in a different ethnic group, African-Americans, and determine whether and how these gene sets impact psychotic disconnectivity. African-Americans, an underserved population, have ~32% more highly deleterious non-synonymous rare variants in these networks than individuals of European ancestry, improving our power to detect rare variants. Our aims are to: (1) use modern MRI acquisition and analysis techniques based on the Human Connectome Project to document psychotic disconnectivity in 750 African Americans (375 with a psychotic disorder and 375 demographically matched comparison subjects). We will test hypotheses that diagnostic and dimensional indices of psychosis are associated with reduced global functional connectivity but intact global structural connectivity, combined with aberrant connectivity between specific regions or tracts; (2) conduct whole exome sequencing (WES) to test the influence of rare non-synonymous variants from genes in previously identified gene sets on psychosis risk using a network-centered analysis strategy. We will test hypotheses that the voltage-gated calcium ion channel, and the ARC-associated scaffold protein and the NMDAR postsynaptic signaling complexes influence diagnostic and dimensional indices of psychosis; and (3) apply this same network-centric test to determine if gene sets implicated in illness risk also influence functional and structural psychotic disconnectivity. Linking these genetic pathways to psychotic disconnectivity will provide mechanistic insights into the genomic influences on psychotic illness. Our collaborative application includes sites at Yale/Hartford Hospital (DC Glahn PI), Stanford (RA Poldrack PI) and Texas Biomedical Research Institute (J Blangero PI). Our results should bolster our understanding of the genetic architecture of psychotic illness and provide important clues for traversing the chasm between identified genetic networks and the behaviorally defined disorder.