BIPOLAR ENDOPHENOTYPES IN POPULATION ISOLATES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 本研究旨在识别与双相情感障碍(BP)相关的可遗传数量性状(内表型)，然后利用这些内表型进行连锁和关联分析，以确定一系列特征良好的扩展家系中的数量性状基因座(QTL)。这是假设，内表型可能比临床表型更强大的遗传图谱。第一步是测量选定的神经解剖学、神经认知、气质和活动相关特征，这些特征以前显示或假设与BP有关。这些特征将使用高分辨率结构磁共振成像(MRI)脑扫描进行测量，并广泛用于神经认知、气质和活动的季节性/昼夜变化的量表。调查小组在使用这些评估工具方面有相当丰富的经验。 将对来自安蒂奥基亚(哥伦比亚)和哥斯达黎加遗传隔离人口的11个扩展家系的约400名成员进行这些特征的聚合评估。这些家系是根据他们的包括多个患有严重BP(BP-I)的个体而确定的。因此，这些家系应该丰富存在与BP相关的等位基因，以反映先前的内表型特征。任何显示家族聚集性的内表型都将被用于全基因组范围的QTL连锁和关联分析，使用我们将在本项目中获得的全基因组范围的高分辨率基因类型(单核苷酸多态，SNP)。这项研究将利用这些家系的特征良好的家系以及合作小组成员已经对这些家系进行的广泛的家谱和临床表征。这两个研究群体的遗传同质性应该会增加该项目识别与BP相关的QTL的可能性。未来的研究将使用QTL来识别可能揭示BP病理生理学的序列变异。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This proposal is to identify heritable, quantitative traits (endophenotypes) that are related to bipolar disorder (BP) and then to use these endophenotypes for linkage and association analyses to identify quantitative trait loci (QTL) in a series of well characterized extended pedigrees. It is hypothesized that the endophenotypes may be more powerfully genetically mapped than the clinical phenotype. The first step is to measure selected neuroanatomical, neurocognitive, temperament, and activity related features previously shown or hypothesized to be associated with BP. These features will be measured using high resolution structural magnetic resonance imaging (MRI) brain scans, and widely used scales for neurocognition, temperament, and seasonal/circadian variation in activity. The investigative team has considerable experience in using these assessment tools. Aggregation of each of these features will be assessed in about 400 members of 11 previously investigated extended pedigrees from the genetically isolated populations of Antioquia (Colombia) and Costa Rica. These pedigrees were ascertained based on their including multiple individuals affected with severe BP (BP-I). Therefore, these pedigrees should be enriched for the presence of BP-associated alleles for the previous endophenotypic features. Any of the endophenotypes that demonstrate familial aggregation will be used for genomewide QTL linkage and association analysis of the complete pedigrees using high-resolution genomewide genotypes (for single nucleotide polymorphisms, SNP's) that we will obtain in this project. The study will take advantage of the well-characterized pedigrees and extensive genealogical and clinical characterization already undertaken by members of the collaborative team on these pedigrees. The genetic homogeneity of the two study populations should enhance the probability that this project will identify QTL associated with BP. Future studies will use the QTL to identify sequence variants that may shed light on the pathophysiology of BP.