Genome Sequencing in Extended Bipolar Pedigrees

描述（由申请人提供）：本项目将应用全基因组测序（WGS），在一组特征异常良好的扩展家系中全面鉴定导致重度双相情感障碍（BP-I）风险的遗传变异。BP是一种常见的、严重的精神综合征，具有高度遗传性，但在病因学上具有异质性。我们的合作团队已经获得资助，进行广泛的表型分析（用于BP-I诊断和定量测量，测定BP的生物学基础，即内表型）和基于26个家系中850个个体的密集SNP基因分型的全基因组连锁和关联分析。这些家系均包含多个BP-1感染个体，来自哥斯达黎加（CVCR）和哥伦比亚安蒂奥基亚（ANT）的中央谷相关人群分离株。我们现在建议对来自这些家族的450个个体进行深度WGS; WGS数据将用于估算整个基因分型个体组中的综合基因组范围变异。将进行统计学和生物信息学分析，以优先考虑在独立研究样本中复制最有可能促成BP-I或BP相关内表型的变体。该项目的数据将迅速与科学界分享，为旨在更好地理解、治疗和预防精神障碍的努力提供独特的资源。

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.