The Bipolar Sequencing Consortium for Combined Analyses and Follow-Up

用于组合分析和随访的双极测序联盟

• 批准号: 9156179
• 负责人: MICHAEL L BOEHNKE
• 金额: $ 89.54万
• 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 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9156179
• 关键词: Affect; Architecture; Biological; Bipolar Disorder; Case-Control Studies; Collaborations; Collection; Communities; Complex; 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; Investments; Joints; Mental disorders; Minor; Molecular; Mood Disorders; National Institute of Mental Health; Play; Prevention strategy; Proteomics; Public Health; Reporting; Research; Research Design; Research Infrastructure; Research Personnel; Resource Sharing; Resources; Risk; Role; Sampling; Schizophrenia; Susceptibility Gene; Technology; Testing; Variant; Work; case control; data sharing; disorder control; disorder risk; exome sequencing; follow-up; genetic association; genetic variant; genome sequencing; genome wide association study; improved; meetings; neurobiological mechanism; next generation sequencing; rare variant; research study; 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）的关键支持，该联盟汇集了 来自全国各地和国际上的领先研究人员正在进行外显子组和基因组 双相情感障碍（BD）的测序研究。BD是一种破坏性的情绪障碍， 公共卫生负担。它是最具遗传性的严重精神障碍之一，估计高达 百分之九十然而，在识别BD易感基因方面的成功明显落后于其他严重的精神疾病， 精神分裂症等疾病。在该提议中，BSC将共享资源和序列数据， 联合分析，将推进BD的遗传病因学研究，其规模是每个人都不可能的。 研究小组自己工作。精神病基因组学联盟（PGC） 使用全基因组关联研究（GWAS）已经开始暗示常见的遗传变异的风险， 对于BD。然而，GWAS遗漏了次要等位基因频率<1%的罕见遗传变异的贡献。它 假设罕见的遗传变异可能进一步导致复杂疾病的遗传性， BD，并且鉴定更罕见的遗传变异可能更直接地涉及潜在的生物学特性。 BD的病因学机制。下一代测序技术的进步 越来越有可能在大量个体中对外显子组或整个基因组进行测序， 具有成本效益的方式。有了这项技术，研究现在可以询问遗传变异的全谱 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， 在有多个患病亲属的家庭或大量无关病例和对照组中研究BD。在 根据这项提议，我们将收集BD上现有最大的测序数据， 对来自5项不同病例对照测序研究的超过4，700例病例和9，000例对照进行了综合分析 以及来自10个家庭测序研究的200多个家庭和1,000多名受影响的亲属。我们将整合 结合其他正在进行的基因组、转录组和蛋白质组研究的结果， 阐明罕见变异在BD遗传结构中的作用，并表征BD的分子和 神经生物学机制，涉及罕见的变异和基因可能有助于BD的风险。我们 然后，我们将跟踪我们分析的主要结果，并在超过5000个独立样本中进行测试 通过一个新的全基因组测序计划，我们可以获得病例和对照。所有 合并分析的汇总数据和结果将通过在线研究资源免费共享， 研究界。下一代测序技术在揭示基因组中的 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/预防战略的基础。