Scalable tool and comprehensive maps to interpret structural variation across the neuropsychiatric spectrum

摘要 结构变异(Sv)，定义为≥50dna核苷酸的重排，是遗传基因的主要来源 人类之间的多样性和神经精神障碍(NPD)架构的一个重要组成部分。 尽管它们在病因学上具有重要意义，但人们对SV形成的后果知之甚少。 基因组，因为缺乏准确的衡量方法来评估得失对全基因组的影响 DNA(‘剂量敏感性’)。相比之下，基因突变不耐受的稳健模型是从 单核苷酸变异(SNV)，在基因组中出现的频率是SVS的~200倍。这些 针对基因内功能丧失突变(例如，来自基因组的LOEUF)的负选择度量 聚合数据库[gnomAD])对跨NPD和孟德尔人的基因和基因座发现至关重要 精神错乱。相比之下，缺乏针对SVS的同等措施阻碍了发现。这一更新寻求 在基础工具的基础上，完成了基因组变异图和跨NPD的关联研究 在最初的资助期内，到现在定义全球不同人群中的SVS前景，并 确定他们对个体和跨障碍NPD风险的相对贡献。为了实现这些目标， 我们将利用由我们的成员领导的大规模生物库和NPD研究计划的结合 与研究团队一起开发可扩展到数百万人的新工具和资源。我们会 首先聚合和协调使用我们的GATK-SV和GATK-gCNV工具生成的整个2.6版的SV调用集 具有基因组和外显子组测序数据的百万个样本，以创建跨不同领域的广泛SV图谱 人口。然后，我们将应用新的统计方法来预测SV变异率，并建立 全基因组剂量敏感性(目标1)。这些新的SV变体类别和剂量敏感性指标将 纳入以家庭为基础的非传染性疾病和病例对照关联研究，涉及387,675例正在进行的病例 队列收集(目标2)。值得注意的是，这些数据集将包括由我们团队成员领导的重要计划 调查目前在新产品开发中代表性不足的不同人群的新产品开发维度 学习。最后，我们将使用创新的新方法来调查SVS的影响，这些影响一直是未知的 从现有技术中发现，但现在可以进行长读测序，我们将应用新的 分析方法，探讨其对非传染性疾病的潜在影响(目标3)。总体而言，每个目标都解决了一个当前 神经精神病学基因组学领域的空白和任何一个领域的成功都将代表着 菲尔德。我们已经组建了一支优秀的专家团队，涵盖了计算和统计的所有领域 基因组学，以及神经精神疾病的表型维度，在其结论中 提案将以前所未有的规模产生新的工具和资源，以定义 目前尚不清楚NPD的遗传结构。

ABSTRACT Structural variants (SVs), defined as rearrangements of ≥50 DNA nucleotides, are a major source of genetic diversity among humans and an important component of the architecture of neuropsychiatric disorders (NPDs). Despite their etiological significance, remarkably little is known about the consequences of SV formation across the genome as there is a dearth of accurate measures to assess the genome-wide impact of gains or losses of DNA (‘dosage sensitivity’). In contrast, robust models of mutation intolerance in genes have been derived from single nucleotide variants (SNVs), which occur at ~200-fold higher frequency in the genome than SVs. These metrics of negative selection against loss-of-function mutations within genes (e.g., LOEUF from the genome aggregation database [gnomAD]) have been critical to gene and locus discovery across NPDs and Mendelian disorders. By contrast, the absence of equivalent measures for SVs has hindered discovery. This renewal seeks to build on the foundational tools, maps of genomic variation, and association studies across NPDs completed during the initial funding period to now define the landscape of SVs across diverse global populations and determine their relative contribution to the individual and cross-disorder NPD risk. To accomplish these goals, we will leverage the coalescence of massive-scale biobank and NPD study initiatives led by members of our research team with the development of new tools and resources that can scale to millions of individuals. We will first aggregate and harmonize SV callsets generated using our GATK-SV and GATK-gCNV tools across >2.6 million samples with genome and exome sequencing data to create expansive SV maps across diverse populations. We will then apply new statistical approaches to predict SV mutation rates and develop models of genome-wide dosage sensitivity (Aim 1). These new SV variant classes and dosage sensitivity metrics will be integrated into family-based and case-control association studies of NPDs across 387,675 cases from ongoing cohort collections (Aim 2). Notably, these datasets will include significant initiatives led by members of our team to investigate the dimensions of NPDs across diverse populations that are currently under-represented in NPD studies. Finally, we will use innovative new approaches to investigate the influence of SVs that have been cryptic to discovery from existing technologies but are now accessible to long-read sequencing and we will apply new analysis methods to explore their potential influence on NPDs (Aim 3). Overall, each aim addresses a current void in neuropsychiatric genomics and success in any one area would represent an important advance for the field. We have assembled an outstanding team of experts across all domains of computational and statistical genomics, as well as the phenotypic dimensions of neuropsychiatric conditions, and at its conclusion this proposal will yield novel tools and resources at an unprecedented scale to define an important component of the currently unexplained genetic architecture of NPDs.