Anxiety Trait as a Quantitative Behavioral Marker for Bipolar Disorder.

摘要： 双相情感障碍(BP)是一种发病率很高的精神疾病，占人类总数的1%到4% 人口。大多数患者都会持续出现精神症状、生产力丧失和 功能性。尽管对双极表型进行了广泛的遗传研究，而且还有一些有趣的连锁和 协会的调查结果发现，识别这种疾病的特定基因一直很困难。搜索 因为BP涉及的遗传位点可能受到疾病的复杂性和治疗困难的阻碍 定义BP频谱。阐明BP基因结构的主要问题之一是 BP分类诊断似乎不能很好地预测表型和 导致个体患BP风险的特定基因变异。因此，指标 在基因型和表型(内表型)之间进行调节的过程对于解决 家系成员在BP遗传学研究中的相互矛盾的诊断状态。这种生物标志物代表了一种 了解BP背后受基因影响的生物过程的窗口。内表型可能代表一个 更简单、更易处理的病因，可以通过强大的分析进行定量测量和分析 对于定性的表型标记物，如诊断类别，缺乏现成的策略。我们有 进行了一项初步研究，以调查焦虑的量化测量作为候选内表型 对BP家系的BPI进行遗传度分析、遗传相关分析及与BPI的关联分析。我们发现 状态和特质焦虑的量化测量具有高度的遗传性，具有某些遗传因素，而且 焦虑特质与BPI相关。目前的建议打算进一步检查焦虑特征在一个 来自相似遗传和文化环境的BPI扩展家系的更大样本(哥斯达黎加 中央山谷人口)。我们将确定30个新的扩展家系(600个个体)，至少 1名被诊断患有BPI(基于DSMIV的共识诊断)和60名健康无关的人 控制。量化焦虑将通过使用状态-特质焦虑问卷和其他 与焦虑相关的自评人格量表将被用来将焦虑描述为一种潜在的。我们将测试 焦虑是否符合作为BPI内表型的验证标准 由SOLAR软件包提供的统计分析。我们将收集血液样本和其他 目前提议的范围：将对所有受试者进行完整的基因组筛查(660个新的 来自我们初步研究的566个个体和566个老对象)以及QTL连锁和关联分析。我们 假设我们将识别包含特定于这些定量测量的基因的区域 样本，以及影响BPI焦虑成分的主要效应的特定候选基因。

Summary: Bipolar Disorder (BP) is a psychiatric illness with high morbidity, affecting from 1 to 4 % of all human populations. Most patients experience continued difficulty with psychiatric symptoms, lost productivity and functionality. Despite extensive genetic studies of the bipolar phenotype, and some interesting linkage and association findings identification of specific genes underlying the disorder have been difficult. The search for the genetic loci involved in BP has likely been hampered by the complexity of the illness and difficulty in defining the BP spectrum. One of the main problems in elucidating the genetic architecture of BP is the fact that the BP categorical diagnosis appears to be a poor predictor of correlation between the phenotype and the specific genotypic variants which contribute to an individual's risk of developing BP. Hence, indicators of processes mediating between genotype and phenotype (endophenotypes) are necessary to resolve the conflicting diagnostic status of family members in genetic studies of BP. Such biomarkers represent a window into the genetically influenced biological process underlying BP. Endophenotypes may represent a simpler and tractable etiology that can be quantitatively measured and analyzed with powerful analysis strategies not readily available for qualitative phenotypic markers such as diagnostic category. We have conducted a pilot study to investigate a quantitative measure of anxiety as a candidate endophenotype for BPI in BP families, by analyzing the heritability, genetic correlation and association with BPI. We found that quantitative measurements of state and trait anxiety are highly heritable, share some genetic factors and that the anxiety trait is associated with BPI. The current proposal intends to further examine anxiety trait in a larger sample of BPI extended pedigrees from a similar genetic and cultural environment (Costa Rican Central Valley population). We will ascertain 30 new extended pedigrees (600 individuals) with at least one individual diagnosed with BPI (by consensus diagnosis based on DSMIV) and 60 healthy unrelated controls. Quantitative anxiety will be evaluated by using the State-Trait Anxiety Inventory and additional self-rated anxiety related personality scales will be used to characterize anxiety as a potential. We will test whether anxiety fulfill the validation criteria to be an endophenotype for BPI by using specialized statistical analyses provided by SOLAR Software Package. We will collect blood specimens and beyond the scope of the current proposal: a complete genome screen will be conducted for all subjects (660 new individuals and 566 old subjects from our pilot study,) and QTL linkage and association analyses as well. We hypothesize that we will identify regions containing genes specific for these quantitative measures in the sample, as well as specific candidate genes of major effect underlying the anxiety component of BPI.