Bipolar & Schizophrenia Consortium for Parsing Intermediate Phenotypes

双极性

• 批准号: 7906718
• 负责人: GUNVANT K THAKER
• 金额: $ 89.61万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-28 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7906718
• 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

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）可能有重叠的病因决定因素。确定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。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，改变大脑解剖结构，行为和功能障碍的因果路径。平行的努力已经确定并完善了几种稳定的、可遗传的、具有（部分）已知生物底物的替代性内表型，并且与精神病易感性相关。虽然许多这样的内源性表型已单独研究SZ，并在较小程度上在BP，没有研究全面评估了广泛的面板，这些标志物在这两种疾病的平行招聘，以及在何种程度上，他们标志着独立方面的精神病风险，或其重叠的两种疾病。这一系列的研究将可能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性进展，并指导针对特定缺陷的新的特异性治疗方法的开发。拟议研究的总体目标是在精神分裂症和双相情感障碍患者及其未受影响的亲属中检查一组广泛的推定内表型，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; 3）对比两种疾病内表型的遗传性。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（患有精神病）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的测量结果（例如，眼跟踪、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），和脑结构（例如，特定脑区域中的灰色和白色物质的体积）。我们将为将来的基因研究收集血液。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家族内的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，并澄清有关病理生理学的共同和不同方面的概念，疾病内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病性障碍的临床界限。这项研究将由5个经验丰富的研究小组进行，这些研究小组具有长期密切且富有成效的合作历史。 公共卫生相关性：这个多地点项目将确定内在表型（或责任标记），在精神分裂症和双相情感障碍中是共享的和不同的。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共同和不同方面的概念，疾病内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病性障碍的临床界限。

项目成果

A CHRNA5 allele related to nicotine addiction and schizophrenia.

• DOI: 10.1111/j.1601-183x.2011.00689.x
• 发表时间: 2011-07
• 期刊: Genes, brain, and behavior
• 作者: Hong LE;Yang X;Wonodi I;Hodgkinson CA;Goldman D;Stine OC;Stein ES;Thaker GK
• 通讯作者: Thaker GK

Prefrontal brain network connectivity indicates degree of both schizophrenia risk and cognitive dysfunction.

• DOI: 10.1093/schbul/sbt077
• 发表时间: 2013-09
• 期刊: Schizophrenia bulletin
• 影响因子: 6.6
• 作者: P. Unschuld;Alison S Buchholz;M. Varvaris;Peter C. M. van Zijl;C. Ross;J. Pekar;C. Hock;J. Sweeney;C. Tamminga;M. Keshavan;G. Pearlson;G. Thaker;D. Schretlen

Subtyping Schizophrenia Patients Based on Patterns of Structural Brain Alterations.

• DOI: 10.1093/schbul/sbab110
• 发表时间: 2021-09
• 期刊: Schizophrenia bulletin
• 影响因子: 6.6
• 作者: Yuan Xiao;W. Liao;Zhiliang Long;B. Tao;Qiannan Zhao;C. Luo;C. Tamminga;M. Keshavan;G. Pearlson;B. Clementz;E. Gershon;E. Ivleva;S. Keedy;B. Biswal;A. Mechelli;R. Lencer;J. Sweeney;S. Lui;Q. Gong