BIPOLAR ENDOPHENOTYPES IN POPULATION ISOLATES

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 该建议是确定遗传，数量性状（内表型），与双相情感障碍（BP），然后使用这些内表型的连锁和关联分析，以确定数量性状基因座（QTL）在一系列良好的特点扩展家系。据推测，内表型可能比临床表型更强大的遗传映射。第一步是测量先前显示或假设与BP相关的选定神经解剖学、神经认知、气质和活动相关特征。这些特征将使用高分辨率结构磁共振成像（MRI）脑部扫描和广泛使用的神经认知、气质和活动的季节/昼夜变化量表进行测量。调查组在使用这些评估工具方面有相当丰富的经验。 将在来自安蒂奥基亚（哥伦比亚）和哥斯达黎加遗传隔离人群的11个先前调查的扩展家系的约400名成员中评估这些特征中的每一个的聚集。这些家系是根据其包括多个受严重BP（BP-I）影响的个体而确定的。因此，这些家系应富集BP相关等位基因的存在，为以前的内表型特征。任何表现出家族聚集性的内表型都将用于全基因组QTL连锁和完整家系的关联分析，该分析使用我们将在本项目中获得的高分辨率全基因组基因型（用于单核苷酸多态性，SNP）。该研究将利用这些家系的合作团队成员已经进行的良好特征化的家系和广泛的系谱学和临床特征。两个研究群体的遗传同质性应提高该项目将确定与BP相关的QTL的概率。未来的研究将使用QTL来鉴定可能揭示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.