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）是一种发病率高的精神疾病，影响所有人群的1%至4%。大多数患者都会经历持续的精神症状困难、生产力和功能丧失。尽管对双相情感障碍的表型进行了广泛的遗传学研究，并发现了一些有趣的连锁和相关发现，但很难确定该疾病背后的特定基因。由于疾病的复杂性和难以确定BP谱，对BP相关遗传位点的研究可能受到阻碍。阐明BP遗传结构的主要问题之一是BP分类诊断似乎是表型和特定基因型变异之间相关性的不良预测因子，这有助于个体发展BP的风险。因此，基因型和表型（内表型）之间介导的过程的指标是必要的，以解决BP遗传研究中家庭成员的诊断状态冲突。这些生物标志物代表了一个窗口，以遗传影响的生物过程的基础BP。内表型可能代表一种更简单和易于处理的病因学，可以用定性表型标记物（如诊断类别）不易获得的强大分析策略进行定量测量和分析。我们已经进行了一项试点研究，以调查焦虑作为候选内表型BP家庭的BPI，通过分析遗传力，遗传相关性和与BPI的关联的定量测量。我们发现，状态和特质焦虑的定量测量是高度遗传的，共享一些遗传因素，焦虑特质与BPI相关。目前的建议旨在进一步研究焦虑性状在一个更大的样本BPI扩展谱系从一个类似的遗传和文化环境（哥斯达黎加中央谷人口）。我们将确定30个新的扩展家系（600人），其中至少有一个人诊断为BPI（根据DSMIV的一致诊断）和60个健康的无关对照。将使用状态-特质焦虑量表评估定量焦虑，并使用其他自评焦虑相关人格量表将焦虑表征为潜在焦虑。我们将通过使用SOLAR软件包提供的专门统计分析来测试焦虑是否满足作为BPI内表型的验证标准。我们将收集血液标本，并超出当前提案的范围：将对所有受试者（来自我们的试点研究的660名新个体和566名老受试者）进行全基因组筛查，并进行QTL连锁和关联分析。我们假设，我们将确定区域包含基因的具体这些定量措施的样本，以及具体的候选基因的主要影响的焦虑成分的BPI。 公共卫生相关性：本研究提出了BPI的另一种临床定义，并试图解决其病因学的潜在遗传难题。对BPI和共病焦虑的复杂相互作用的理解为连续双极谱提出了一种新的诊断范式。提高临床分类的准确性将有利于这些患者的治疗方法，并对公共卫生政策产生积极影响。因此，将寻求更有效地分配卫生资源，这对哥斯达黎加这样的社会化公共卫生系统至关重要。

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.