Bipolar & Schizophrenia Consortium for Parsing Intermediate Phenotypes

描述（由申请人提供）：最近的研究提供了大量证据表明精神分裂症（SZ）和精神病性双相情感障碍（BP）可能具有重叠的病因决定因素。确定与疾病相关的遗传效应是SZ和BP研究的主要焦点，对这两种疾病的诊断和治疗具有重大意义。这方面的努力是多方面的，其最终目标是描述从特定基因变异到神经元功能变化、大脑解剖结构改变、行为和功能障碍的因果关系。平行的努力已经确定并完善了几种稳定的、可遗传的、（部分）已知的生物底物和与精神病倾向相关的替代内表型。尽管许多这样的内表型在SZ中被单独研究过，在BP中也有较少的研究，但还没有研究全面评估这两种疾病中平行募集的这些标志物的广泛面板，以及它们在多大程度上标记了精神病风险的独立方面，或者它们在两种疾病中的重叠。这条研究路线将潜在地影响我们对精神疾病的概念化，帮助我们在识别精神病的病理生理学方面取得关键进展，并指导针对特定缺陷的新的特定治疗方法的发展。拟议研究的总体目标是检查受影响的精神分裂症和双相情感障碍患者及其未受影响的亲属的广泛假定的内表型，以便：1)表征SZ和精神病性BP之间家族表型重叠的程度；2)确定两种疾病特有的内表型模式，3)对比两种疾病内表型的遗传性。为了达到这些目标，我们将从五个中心招募500名SZ和500名BP I（有精神病）先证者，约1700-2000名这些先证者的一级亲属，以及500名不相关的非精神病对照。我们将获得神经生理学（例如，眼动追踪、P50门控、PPI和P300）、神经认知（例如，注意力/警惕性、情景记忆和工作记忆）和大脑结构（例如，特定大脑区域的灰质和白质体积）的测量结果。我们将采集血液用于未来的基因研究。我们将评估SZ和BP亲属中内表型的家族聚集程度。建立SZ和BP家族内表型特征的相似性和差异性将为未来的遗传学研究提供重要见解，并澄清病理生理学的共同和独特方面的概念，疾病内部潜在的有意义的异质性，以及成人精神病学中两种最常见的精神疾病的临床界限。这项研究将由5个经验丰富的研究小组进行，他们有着长期密切和富有成效的合作历史。

DESCRIPTION (provided by applicant): Recent studies provide considerable evidence that schizophrenia (SZ) and psychotic bipolar disorder (BP) may share overlapping etiologic determinants. Identifying disease-related genetic effects is a major focus in SZ and BP research, with enormous implications for diagnosis and treatment for these two disorders. Efforts have been multifaceted, with the ultimate goal of describing causal paths from specific genetic variants, to changes in neuronal functioning, to altered brain anatomy, to behavioral and functional impairments. Parallel efforts have identified and refined several alternative endophenotypes that are stable, heritable, have (partly) known biological substrates, and are associated with psychosis liability. Although many such endophenotypes have been individually studied in SZ, and to a lesser extent in BP, no study has comprehensively assessed a broad panel of these markers in the two disorders with parallel recruitment, and the extent to which they mark independent aspects of psychosis risk, or their overlap in the two disorders. This line of investigation will potentially impact our conceptualization of psychotic disorders, help us make critical strides to identify the pathophysiology of psychosis, and guide development of new specific treatments targeting particular deficits. The overall goal of the proposed research is to examine a broad panel of putative endophenotypes in affected individuals with schizophrenia and bipolar and their unaffected relatives in order to: 1) characterize the degree of familial phenotypic overlap between SZ and psychotic BP; 2) identify patterns of endophenotypes unique to the two disorders, and 3) contrast the heritability of endophenotypes across the disorders. To achieve these goals, we will recruit 500 SZ and 500 BP I (with psychosis) probands, ~1700-2000 1st degree relatives of these probands, and 500 unrelated non-psychiatric controls from five centers. We will obtain measures of neurophysiology (e.g., eye tracking, P50 gating, PPI, and P300), neurocognition (e.g., attention/vigilance, episodic and working memory), and brain structure (e.g., volumes of gray and white matter in specified brain regions). We will collect blood for future genetic studies. We will assess the degree of familial aggregation of endophenotypes in SZ and BP relatives. Establishing similarities and differences in the endophenotypic signatures within SZ and BP families will provide important insights for future genetic studies, and clarify concepts about common and distinct aspects of pathophysiology, potentially meaningful heterogeneity within disorders, and the clinical boundaries of the two commonest psychotic disorders in adult psychiatry. This research will be conducted by 5 experienced research groups, with a long history of close and productive collaboration. Public Health Relevance: This multisite project will identify endophenotypes (or liability markers) that are shared and different in schizophrenia and bipolar disorder. Findings from these studies will provide important insights for future genetic studies, and clarify concepts about common and distinct aspects of pathophysiology, potentially meaningful heterogeneity within disorders, and the clinical boundaries of the two commonest psychotic disorders in adult psychiatry.