The Bipolar Sequencing Consortium for Combined Analyses and Follow-Up - Supplement

用于组合分析和随访的双极测序联盟 - 补充

• 批准号: 9479336
• 负责人: MICHAEL L BOEHNKE
• 金额: $ 18.88万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9479336
• 关键词: Affect; Architecture; Biological; Bipolar Disorder; Case Study; Case-Control Studies; Collaborations; Collection; Communities; Complex; Controlled Study; Country; Data; Data Analyses; Data Set; Disease; Ensure; Etiology; Extended Family; Family; Family Study; Foundations; Gene Frequency; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genomics; Goals; Heritability; Individual; International; Investments; Joints; Mental disorders; Minor; Molecular; Mood Disorders; National Institute of Mental Health; Play; Prevention strategy; Proteomics; Public Health; Reporting; Research; Research Infrastructure; Research Personnel; Resource Sharing; Resources; Risk; Role; Sampling; Schizophrenia; Susceptibility Gene; Technology; Testing; Variant; Work; case control; data sharing; design; disorder control; disorder risk; exome; exome sequencing; experimental study; follow-up; genetic association; genetic variant; genome sequencing; genome wide association study; improved; neurobiological mechanism; next generation sequencing; online resource; rare variant; severe mental illness; success; transcriptomics; whole genome; working group

This proposal seeks crucial support for The Bipolar Sequencing Consortium (BSC), which brings together leading researchers from around the country and internationally who are carrying out exome and genome sequencing studies of bipolar disorder (BD). BD is a devastating mood disorder that imposes a significant burden on public health. It is among the most heritable serious mental disorders, with estimates ranging up to 90%. Yet, success in identifying susceptibility genes for BD has lagged noticeably behind other serious mental disorders such as schizophrenia. In this proposal, the BSC will share resources and sequence data for combined analyses that will advance the search for the genetic etiology of BD at a scale not possible by each of the research groups working by themselves. Recent efforts by the Psychiatric Genomics Consortium (PGC) using genome-wide association studies (GWAS) have begun to implicate common genetic variation in the risk for BD. However, GWAS miss the contribution of rarer genetic variation with minor allele frequencies <1%. It is hypothesized that rarer genetic variation may further contribute to the heritability of complex disorders like BD, and that identification of rarer genetic variation may more directly implicate underlying biological mechanisms in the etiology of BD. Advances in next generation sequencing technology are making it increasingly possible to sequence the exome or entire genome in large numbers of individuals in a costeffective manner. With this technology, studies can now interrogate the full spectrum of genetic variation and correlate it with disease. Researchers in the BSC are taking advantage of next generation sequencing to study BD in families with multiple affected relatives or in large numbers of unrelated cases and controls. In this proposal, we will assemble the largest existing collection of sequencing data on BD and carry out combined analyses of over 4,700 cases and 9,000 controls from 5 different case-control sequencing studies and over 200 families with over 1,000 affected relatives from 10 family sequencing studies. We will integrate the findings from the combined analyses with other on-going genomic, transcriptomic and proteomic studies to clarify the role of rare variants in the genetic architecture of BD and characterize the molecular and neurobiological mechanisms by which implicated rare variants and genes may contribute to risk for BD. We will then follow-up the top findings from our analyses and test them in an independent sample of over 5,000 cases and controls that will be made available to us through a new whole genome sequencing initiative. All summary data and results from the combined analyses will be freely shared via an on-line study resource with the research community. Next generation sequencing technology holds great promise for revealing the genetic architecture of complex psychiatric disorders. This proposal will build on the NIMH's considerable investment in sequencing to maximize our ability to explain the genetic contribution to BD and lay the needed foundation for improved treatment/prevention strategies.

该提案寻求双极测序联盟 (BSC) 的重要支持，该联盟汇集了 来自全国各地和国际上正在进行外显子组和基因组研究的领先研究人员 双相情感障碍（BD）的测序研究。 BD 是一种毁灭性的情绪障碍，会严重影响 公众健康的负担。它是最具有遗传性的严重精神障碍之一，估计高达 90%。然而，在识别 BD 易感基因方面所取得的成功却明显落后于其他严重精神疾病。 精神分裂症等疾病。在该提案中，BSC将共享资源和序列数据 综合分析将推动对 BD 遗传病因学的探索，其规模是各自不可能达到的 研究小组独立工作的情况。精神病学基因组学联盟 (PGC) 最近的努力 使用全基因组关联研究（GWAS）已开始将常见的遗传变异与风险联系起来 对于BD。然而，GWAS 忽略了较小等位基因频率 <1% 的罕见遗传变异的贡献。它 假设更罕见的遗传变异可能进一步促进复杂疾病的遗传性，例如 BD，并且鉴定更罕见的遗传变异可能更直接地暗示潜在的生物学 BD 病因学机制。下一代测序技术的进步正在使其成为可能 对大量个体的外显子组或整个基因组进行测序的可能性越来越大 具有成本效益的方式。有了这项技术，研究现在可以询问全谱的遗传变异 并将其与疾病联系起来。 BSC 的研究人员正在利用下一代测序技术 在有多个受影响亲属的家庭或大量不相关的病例和对照中研究 BD。在 根据该提案，我们将收集 BD 上现有最大的测序数据集并进行 对来自 5 个不同病例对照测序研究的 4,700 多个病例和 9,000 个对照进行综合分析 以及来自 10 项家庭测序研究的 200 多个家庭（拥有 1,000 多名受影响亲属）。我们将整合 与其他正在进行的基因组、转录组和蛋白质组研究相结合的分析结果 阐明罕见变异在 BD 遗传结构中的作用，并表征其分子和特征 涉及罕见变异和基因的神经生物学机制可能会导致双相情感障碍的风险。我们 然后，我们将跟踪我们分析的主要发现，并在超过 5,000 个独立样本中进行测试 我们将通过新的全基因组测序计划向我们提供病例和对照。全部 综合分析的汇总数据和结果将通过在线研究资源与 研究界。下一代测序技术有望揭示 复杂精神疾病的遗传结构。该提案将建立在 NIMH 的大量 投资于测序，以最大限度地提高我们解释 BD 遗传贡献的能力，并奠定所需的基础 改善治疗/预防策略的基础。