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Bipolar & Schizophrenia Consortium for Parsing Intermediate Phenotypes

双极性

基本信息

批准号：
7678495
负责人：
GUNVANT K THAKER
金额：
$ 88.63万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-28 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7678495
关键词：
Adult Affect Amygdaloid structure Anatomy Animal Model Attention Behavioral Biological Bipolar Disorder Blood Blood specimen Brain Brain region Candidate Disease Gene Clinical Cognitive Collaborations Collection Consent Data Development Diagnosis Diagnostic Disease EP300 gene Episodic memory Evaluation Exhibits Eye Factor Analysis Family Family member First Degree Relative Functional disorder Future Genes Genetic Genotype Goals Gray unit of radiation dose Heritability Heterogeneity Hippocampus (Brain)Human Individual Interview Investigation Knowledge Laboratory Procedures Laboratory Study Lateral Measures Methods Neurobiology Neurocognition Neurocognitive Neurons Normal Range Patients Pattern Pharmaceutical Preparations Pharmacology Phenotype Physiological Prefrontal Cortex Problem Solving Psychiatry Psychotic Disorders Recording of previous events Recruitment Activity Recurrence Relative (related person)Research Resources Risk Risk Estimate Sampling Schizophrenia Schizotypal Personality Disorder Short-Term Memory Site Smooth Pursuit Specific qualifier value Structure Subgroup Superior temporal gyrus Symptoms TNFRSF5 gene Temporal Lobe Testing Thalamic structure Validation Ventricular cohort disorder risk endophenotype experience functional disability genetic variant gray matter improved insight millisecond neural circuit neurophysiology oculomotor predictive pursuit proband public health relevance response trait vigilance white matter

项目摘要

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.

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。识别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巨大影响。人们的努力是多方面的，最终目标是描述从特定遗传变异到神经元功能变化、大脑解剖结构改变、行为和功能障碍的因果路径。并行的努力已经确定并完善了几种替代的内表型，这些内表型是稳定的、可遗传的、具有（部分）已知的生物底物，并且与精神病倾向相关。尽管许多此类内表型已在 SZ 中进行了单独研究，并且在 BP 中进行了较小程度的研究，但没有研究全面评估这两种疾病中平行招募的这些标记物的广泛组，以及它们在多大程度上标记精神病风险的独立方面，或它们在两种疾病中的重叠。这一研究方向可能会影响我们对精神障碍的概念化，帮助我们在确定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具体治疗方法的开发。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的亲属的一系列假定的内表型，以便：1）表征 SZ 和精神病性 BP 之间的家族表型重叠程度； 2) 识别两种疾病特有的内表型模式，以及 3) 对比不同疾病的内表型遗传力。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（患有精神病）先证者、这些先证者的约 1700-2000 名一级亲属以及 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/警觉性、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）的测量值。我们将收集血液用于未来的基因研究。我们将评估 SZ 和 BP 亲属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将为未来的遗传学研究提供重要的见解，并澄清有关病理生理学的共同和独特方面的概念、疾病内潜在有意义的异质性以及成人精神病学中两种最常见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，这些研究小组有着长期密切而富有成效的合作历史。公共卫生相关性：这个多站点项目将识别精神分裂症和躁郁症中共有和不同的内表型（或责任标记）。这些研究的结果将为未来的遗传学研究提供重要的见解，并澄清有关病理生理学的常见和独特方面的概念、疾病内潜在有意义的异质性以及成人精神病学中两种最常见精神疾病的临床界限。