Anxiety Trait as a Quantitative Behavioral Marker for Bipolar Disorder.

描述(申请人提供)：双相情感障碍(BP)是一种发病率很高的精神疾病，影响到人类总人口的1%至4%。大多数患者都经历了精神症状、生产力和功能丧失的持续困难。尽管对双相表型进行了广泛的遗传学研究，并有一些有趣的连锁和关联发现，但识别这种疾病的特定基因一直很困难。疾病的复杂性和定义BP谱的困难可能阻碍了对BP所涉及的遗传基因座的搜索。阐明BP遗传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之间的相关性。因此，在BP的遗传学研究中，在基因和表型(内表型)之间调节过程的指示物对于解决家系成员相互矛盾的诊断状态是必要的。这些生物标志物代表了了解BP背后受遗传影响的生物过程的窗口。内表型可能代表了一种更简单、更容易处理的病因学，可以用强大的分析策略进行定量测量和分析，这是定性表型标记物(如诊断类别)所不具备的。我们进行了一项初步研究，通过分析BPI的遗传度、遗传相关性和关联性，探讨焦虑作为BP家族BPI候选内表型的量化指标。我们发现，状态焦虑和特质焦虑的量化测量具有高度的遗传性，分享了一些遗传因素，并且焦虑特质与BPI相关。目前的建议旨在进一步研究来自相似遗传和文化环境(哥斯达黎加中央山谷人口)的BPI扩展家系的更大样本中的焦虑特征。我们将确定30个新的扩展家系(600个个体)，其中至少有一个人被诊断为BPI(基于DSMIV的共识诊断)和60个健康的无血缘关系的对照。量化焦虑将通过使用状态-特质焦虑问卷进行评估，并将使用额外的与焦虑相关的自我评估人格量表来表征焦虑是一种潜在的焦虑。我们将使用SOLAR软件包提供的专门的统计分析来检验焦虑是否满足BPI的内表型验证标准。我们将收集血液样本，并超出当前提议的范围：将对所有受试者(660个新个体和566个来自我们的初步研究的旧受试者)进行完整的基因组筛查，并进行QTL连锁和关联分析。我们假设，我们将在样本中确定包含这些定量指标的特定基因的区域，以及BPI中焦虑成分潜在的主要影响的特定候选基因。 公共卫生相关性：这项研究提出了BPI的另一种临床定义，并打算解决其病因学的潜在遗传学难题。对BPI和共病焦虑的复杂相互作用的理解提出了一种新的连续双极谱诊断范式。提高临床分型的准确性将有利于这些患者的治疗方法，并在公共卫生政策中发挥积极作用。因此，在哥斯达黎加这样的社会化公共卫生系统中，追求更有效的卫生资源分配将是至关重要的。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: This study proposes an alternative clinical definition of BPI and intents to address the underling genetic puzzle of its etiology. The understanding of the complex interplay of BPI and comorbid anxiety raise a new diagnostic paradigm for the continuum bipolar spectrum. Improving accuracy in clinical classification will benefit the therapeutical approach for these patients with positive effect in public health policies. Thus, a more efficiently distribution of health resources will be pursuit which is crucial in a Socialized Public Health System like in Costa Rica.