Anxiety Trait as a Quantitative Behavioral Marker for Bipolar Disorder.

描述（由申请人提供）：双相情感障碍（BP）是一种高发病率的精神疾病，影响所有人口的1%至4%。大多数患者经历精神症状的持续困难，丧失生产力和功能。尽管对双相表现型进行了广泛的遗传研究，并发现了一些有趣的联系和关联，但鉴定这种疾病的特定基因一直很困难。寻找与BP相关的基因位点可能受到疾病复杂性和BP谱定义困难的阻碍。阐明BP遗传结构的一个主要问题是，BP分类诊断似乎不能很好地预测表型和特定基因型变异之间的相关性，而基因型变异会导致个体患BP的风险。因此，基因型和表型（内表型）之间中介过程的指标是解决BP遗传研究中家庭成员诊断地位冲突的必要条件。这些生物标志物为了解BP背后受遗传影响的生物过程提供了一个窗口。内部表型可能代表一种更简单和易于处理的病因学，可以用强大的分析策略进行定量测量和分析，而定性表型标记（如诊断类别）则不容易获得。我们进行了一项初步研究，通过分析遗传力、遗传相关性和与BPI的关联，来调查焦虑作为BP家族BPI候选内表型的定量测量。我们发现状态焦虑和特质焦虑的定量测量具有高度遗传性，共享一些遗传因素，焦虑特质与BPI相关。目前的提案打算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扩展谱系的更大样本的焦虑特征。我们将确定30个新的扩展谱系（600个个体），其中至少有一个个体被诊断为BPI（基于DSMIV的共识诊断）和60个健康的非相关对照。定量焦虑将通过使用状态-特质焦虑量表进行评估，并使用额外的自评焦虑相关人格量表来将焦虑定性为潜在的。我们将使用SOLAR软件包提供的专门统计分析来测试焦虑是否满足BPI的内表型验证标准。我们将收集血液样本，并超出当前提案的范围：将对所有受试者（660名新受试者和566名来自我们的试点研究的老受试者）进行全基因组筛选，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测量特异性基因的区域，以及在BPI焦虑成分基础上起主要作用的特定候选基因。

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.