Genome Sequencing in Extended Bipolar Pedigrees

描述(由申请人提供)：该项目将应用全基因组测序(WGS)来全面识别在一组特征特别好的扩展家系中导致严重双相情感障碍(BP-I)风险的遗传变异。BP是一种常见的严重精神综合征，具有高度的遗传性，但在病因学上具有异质性。我们的合作团队已经得到资助，在26个家系的850个个体中进行广泛的表型分析(BP-I诊断和定量测量分析BP背后的生物学，即内表型)，并进行基于密集SNP基因分型的全基因组连锁和关联分析。这些家系，每个都有多个BP-I感染个体，来自哥斯达黎加中央山谷(CVCR)和哥伦比亚安蒂奥基亚(ANT)的相关种群分离株。我们现在建议对来自这些家庭的450个个体进行深入的WGS；WGS数据将被用于计算整个基因分型个体集合中全面的基因组范围的变异。将进行统计和生物信息学分析，以便优先在独立研究样本中复制最有可能影响BP-I或BP相关内表型的变异。该项目的数据将迅速与科学界共享，为旨在更好地了解、治疗和预防精神障碍的努力提供独特的资源。 公共卫生相关性：传统策略未能成功剖析双相情感障碍(BP)的遗传基础，这是一种毁灭性的、常见的、高度遗传性的精神综合征。该项目将对家系成员的全部基因组进行排序，每个家系成员包括许多患有严重双相情感障碍(BP-I)的个体。通过全面识别这些家系中可能导致BP-I的基因变异，该项目将促进对严重精神障碍的理解、治疗和预防。

DESCRIPTION (provided by applicant): This project will apply whole genome sequencing (WGS) to comprehensively identify the genetic variants contributing to the risk of severe bipolar disorder (BP-I) in an exceptionally well characterized set of extended pedigrees. BP is a common, severe psychiatric syndrome, which is highly heritable yet etiologically heterogeneous. Our collaborative team is already funded to conduct extensive phenotyping (for both the BP-I diagnosis and for quantitative measures that assay the biology underlying BP, i.e. endophenotypes) and genome wide linkage and association analyses based on dense SNP genotyping in 850 individuals in 26 pedigrees. These pedigrees, each with multiple BP-I affected individuals, are drawn from the related population isolates of the Central Valley of Costa Rica (CVCR) and Antioquia, Colombia (ANT). We now propose to conduct deep WGS in 450 individuals from these families; the WGS data will be used to impute comprehensive genome wide variation in the entire set of genotyped individuals. Statistical and bioinformatic analyses will be undertaken to prioritize for replication in independent study samples the variants most likely to be contributing to BP-I or BP-related endophenotypes. The data from this project will be shared rapidly with the scientific community, providing a unique resource for efforts aimed at a better understanding, treatment, and prevention of mental disorders. PUBLIC HEALTH RELEVANCE: Traditional strategies have not succeeded in dissecting the genetic basis of bipolar disorder (BP), a devastating, common, and highly heritable psychiatric syndrome. This project will sequence the whole genomes of members of pedigrees that each include many individuals affected with severe bipolar disorder (BP-I). By comprehensively identifying the genetic variation that could contribute to BP-I in these pedigrees, the project wil advance the understanding, treatment, and prevention of severe mental disorders.