1/2-Whole Genome and Exome Sequencing for Bipolar Disorder

描述（由申请人提供）：本合作R 01提案的目标（由Richard M. Myers和他在HudsonAlpha研究所的同事）的研究是使用高通量DNA测序和基因分型技术来鉴定导致双相情感障碍（BD）风险的基因和途径。这项建议建立在我们在密歇根大学和HudsonAlpha关于BD和其他情绪障碍的小组之间的积极合作的基础上。我们的研究团队结合了高通量遗传学和基因组学的优势，以及创新计算和统计方法的开发和应用，以最大限度地发挥这些新技术的优势。在具体目标1中，我们将对来自2,000个个体的DNA进行测序，其中1,025个患有BD，975个对照，基因组覆盖率> 4倍，44 Mb外显子组平均覆盖率> 60倍。在特定目标2中，我们将基于来自这2，000个样本的序列数据以及来自至少另外6，085个BD病例和7，116个对照GWAS样本的插补数据进行BD关联分析，以在至少7，110个病例和8，091个对照中鉴定BD相关变体。我们将单独分析MAF>0.5%的变体。对于MAF<1%的变异，我们将使用“负担”检验，旨在确定病例中罕见变异簇比对照更常见的区域（反之亦然）。对于插补，我们将使用来自该项目、1000个基因组项目和我们的GoT 2D项目的序列数据作为参考集，并且具有来自先前公布的GWAS的GWAS基因型数据的BD病例对照样本个体作为靶集。在Specific Aim 3中，我们将使用定制的SNP阵列对约5，000个序列变体进行基因分型，并进行深度测序，对7，592个个体中的500个选定基因进行重新测序，其中3，854个患有BD，3，738个对照，并对所得数据进行BD关联分析。该数据集将包括在特定目标1中测序的2，000个个体，以验证基于序列的基因型，以及5，592个额外的个体，以验证基于插补的关联结果和/或加强罕见变异关联的证据。与Pamela Sklar博士合作，我们将通过对32，000例BD病例和30，000例对照进行基因分型来跟踪最有趣的SNP，并对所得数据进行荟萃分析。在具体目标4中，我们将分享数据和方法，以支持BD和其他精神病表型的类似研究，并在科学界更广泛地开展研究。这些目标的实现将为疾病机制提供新的见解，有可能促进BD预防，治疗和诊断的突破。

DESCRIPTION (provided by applicant): The goal of this collaborative R01 proposal (a coordinating proposal is being submitted by Dr. Richard M. Myers and colleagues at HudsonAlpha Institute) is to use high-throughput DNA sequencing and genotyping technologies to identify genes and pathways that contribute to the risk for bipolar disorder (BD). This proposal builds on the active collaboration between our groups at the University of Michigan and HudsonAlpha on BD and other mood disorders. Our research team combines strengths in high-throughput genetics and genomics and development and application of innovative computational and statistical methods to maximize the benefits of these new technologies. In Specific Aim 1, we will sequence DNA from 2,000 individuals, 1,025 with BD and 975 controls, at >4X coverage for the genome and at >60X average coverage for the 44 Mb exome. In Specific Aim 2, we will carry out BD association analyses based on sequence data from these 2,000 samples and imputed data from at least an additional 6,085 BD case and 7,116 control GWAS samples to identify BD- associated variants in at least 7,110 cases and 8,091 controls. We will analyze variants with MAF>0.5% individually. For variants with MAF<1%, we will use "burden" tests designed to identify regions where clusters of rare variants are more common in cases than controls (or vice versa). For imputation, we will use sequence data from this project, the 1000 Genomes Project, and our GoT2D project as reference sets, and BD case- control sample individuals with GWAS genotype data from previously-published GWAS as target sets. In Specific Aim 3, we will use custom SNP arrays to genotype ~5,000 sequence variants and deep sequencing to resequence 500 selected genes in 7,592 individuals, 3,854 with BD and 3,738 controls, and carry out BD association analysis on the resulting data. This set will include the 2,000 individuals sequenced in Specific Aim 1 to validate the sequence-based genotypes and 5,592 additional individuals to validate imputation-based association findings and/or strengthen evidence for rarer variant association. In collaboration with Dr. Pamela Sklar, we will follow-up the most interesting SNPs by genotyping 32,000 BD cases and 30,000 controls and carry out a meta-analysis of the resulting data. In Specific Aim 4, we will share data and methods to support similar studies for BD and other psychiatric phenotypes, and more broadly across the scientific community. Completion of these aims will provide new insights into disease mechanism that have the potential to catalyze breakthroughs in BD prevention, treatment, and diagnosis.