The Bipolar Sequencing Consortium for Combined Analyses and Follow-Up

这项提案寻求对双极测序联盟(BSC)的关键支持，该联盟将 来自全国和国际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是一种毁灭性的情绪障碍，它会给人带来显著的 对公共卫生的负担。它是最易遗传的严重精神障碍之一，估计高达 90%。然而，在识别BD易感基因方面的成功明显落后于其他严重的精神疾病 精神分裂症等精神障碍。在本提案中，BSC将共享资源和序列数据，用于 联合分析将推进对BD遗传病因的研究，这是每个分析都不可能实现的 独立工作的研究小组的成员。精神病学基因组学联盟(PGC)最近的努力 利用全基因组关联研究(GWAS)已经开始将常见的遗传变异与风险联系起来 对于BD来说。然而，GWA忽略了较罕见的等位基因频率为1%的遗传变异的贡献。它 假设更罕见的基因变异可能进一步导致复杂疾病的遗传性，如 BD，识别出更罕见的遗传变异可能更直接地牵涉到潜在的生物学 BD的病因学机制。下一代测序技术的进步正在使它 在大量个体中对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，研究人员现在可以询问基因变异的全部光谱。 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 在有多个受影响亲属的家庭中或在大量无关病例和对照中研究BD。在……里面 这项建议，我们将汇集现有最大的关于BD的测序数据并进行 来自5个不同病例对照测序研究的4700多例病例和9000多名对照的联合分析 以及来自10个家庭测序研究的200多个家庭和1000多个受影响的亲属。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，并表征分子和 涉及罕见变异和基因的神经生物学机制可能导致BD的风险。我们 然后将跟进我们分析得出的最高结果，并在5000多个独立样本中进行测试 病例和对照将通过一项新的全基因组测序计划提供给我们。全 综合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。下一代测序技术有望揭示 复杂精神障碍的遗传结构。这项提议将建立在NIMH相当大的 对测序的投资，以最大限度地提高我们解释BD的基因贡献并奠定所需信息的能力 改善治疗/预防战略的基础。

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.