Bipolar & Schizophrenia Consortium for Parsing Intermediate Phenotypes

描述(由申请人提供)：最近的研究提供了相当多的证据表明，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。识别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巨大的意义。这些努力是多方面的，最终目标是描述从特定遗传变异到神经元功能变化、大脑解剖改变再到行为和功能障碍的因果路径。平行的努力已经确定和提炼了几种可供选择的内表型，这些内表型是稳定的、可遗传的、具有(部分)已知的生物底物，并与精神病易感性有关。尽管许多这样的内表型在深圳被单独研究，在BP中的研究程度较小，但还没有研究全面评估两种疾病中平行招募的广泛的这些标记物，以及它们在多大程度上标志着精神病风险的独立方面，或者它们在两种疾病中的重叠。这一系列研究将潜在地影响我们对精神障碍的概念化，帮助我们在确定精神疾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开发。这项拟议研究的总体目标是检查精神分裂症和双相情感障碍患者及其未受影响亲属的一大批可能的内表型，以便：1)确定SZ和精神病BP之间的家族表型重叠程度；2)确定这两种疾病特有的内表型模式；以及3)比较不同疾病的内表型的遗传性。为了实现这些目标，我们将从五个中心招募500名SZ和500名BP I级(有精神病)先证者，这些先证者的~1700-2000名一级亲属，以及500名无关的非精神科对照。我们将获得神经生理学(例如，眼球跟踪、P50门控、PPI和P300)、神经认知(例如，注意力/警觉性、情景记忆和工作记忆)以及大脑结构(例如，特定大脑区域的灰质和白质体积)的测量结果。我们将为未来的基因研究采集血液。我们将评估SZ和BP亲属内表型的家族聚集程度。确定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的见解，并澄清关于病理生理学的共同和不同方面的概念，疾病中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障碍的临床界限。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。 公共卫生相关性：这个多站点项目将确定精神分裂症和双相情感障碍中共有和不同的内表型(或责任标记物)。这些研究的结果将为未来的遗传学研究提供重要的见解，并澄清关于病理生理学的共同和不同方面的概念，障碍中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障碍的临床界限。

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.