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

描述（由申请人提供）：该合作R01提案的目标（一项协调提案由密歇根大学的Michael Boehnke博士及其同事提交）是使用高通量DNA测序和基因分型技术来识别导致双相情感障碍（BD）风险的基因和途径。这项提议建立在我们在密歇根大学和哈德逊阿尔法研究双相障碍和其他情绪障碍的小组之间积极合作的基础上。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效益。在Specific Aim 1中，我们将对来自2000个个体的DNA进行测序，其中1025个为BD组，975个为对照，基因组覆盖率为104x， 44mb外显子组平均覆盖率为60X。在Specific Aim 2中，我们将根据这2000个样本的序列数据和至少另外6085个BD病例和7116个对照GWAS样本的输入数据进行BD关联分析，以确定至少7110个病例和8091个对照的BD相关变异。我们将分别分析MAF>0.5%的变异。对于MAF<1%的变异，我们将使用“负担”测试来识别罕见变异集群在病例中比对照组更常见的区域（反之亦然）。我们将使用本项目、千人基因组计划和我们的GOT2D项目的序列数据作为参考集，并将来自先前发表的GWAS基因型数据的BD病例对照样本个体作为目标集。在Specific Aim 3中，我们将使用定制的SNP阵列对约5000个序列变异进行基因分型，并对7592名个体、3854名BD患者和3738名对照中的500个选定基因进行深度测序，并对结果数据进行BD关联分析。这一组将包括在Specific Aim 1中测序的2000个个体，以验证基于序列的基因型，以及5,592个额外的个体，以验证基于推测的关联发现和/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，并对结果数据进行荟萃分析。在Specific Aim 4中，我们将分享数据和方法，以支持双相障碍和其他精神病学表型的类似研究，以及更广泛地在科学界进行研究。这些目标的完成将提供对疾病机制的新见解，有可能催化双相障碍预防、治疗和诊断方面的突破。

DESCRIPTION (provided by applicant): The goal of this collaborative R01 proposal (a coordinating proposal is being submitted by Dr. Michael Boehnke and colleagues at the University of Michigan) 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.