Whole genome sequencing of bipolar disorder and schizophrenia

描述(由申请人提供)：我们建议收集和分析有史以来第一个全基因组序列数据，来自精神分裂症(SCZ，n=150)、双相情感障碍(BPD，n=150)和对照组(n=100)的患者。通过首次对精神疾病个体的遗传变异进行全面评估，我们将为未来SCZ和BPD的遗传学研究奠定基础。对于许多常见疾病，大规模全基因组关联研究(GWAS)最近发现了新的遗传风险因素，通常位于以前未被怀疑的基因或非编码区。家族性和双生子研究已经最终确定遗传因素在SCZ和BPD风险中起主要作用，Gwas研究指出罕见的遗传和从头开始的拷贝数变异以及常见的SNPs的重要作用。我们将使用下一代测序技术获得400个样本的全基因组DNA序列。目的1：从18,000个样本中，我们将从瑞典样本中选择SCZ和BPD患者，这些样本富含家族病史，我们为他们配对对照，并从美国样本中为散发性病例选择SCZ和BPD患者，他们的父母DNA样本可用。进行全基因组测序以识别DNA变异。目标2：开发一个分析框架来注释、整理和查询与疾病状态相关的基因数据。目的3：后续测序结果，包括电子基因分型、3000人靶区的深度测序和18,000多人的特定变异基因分型。所有数据和软件工具都将作为资源提供给更广泛的社区。 公共卫生相关性：叙述：我们将使用下一代高通量技术在精神分裂症和双相情感障碍患者和配对对照中获得全基因组序列数据，以寻找可能与这些疾病相关的新的基因变异。它们是影响数百万美国人的重大公共卫生问题，没有有效的治疗方法。

DESCRIPTION (provided by applicant): We propose to collect and analyze the first ever whole genome sequence data from patients with schizophrenia (SCZ, n=150), bipolar disorder (BPD, n=150) and controls (n=100). By providing the first comprehensive evaluation of genetic variation in individuals with psychiatric disease we will lay the foundation for future genetic studies of SCZ and BPD. For many common diseases, large-scale genome-wide association studies (GWAS) have recently identified new genetic risk factors, typically in previously unsuspected genes or non-coding regions. Family and twin studies have conclusively established that heritable factors play the major role in SCZ and BPD risk, and GWAS studies have pointed to important roles for rare inherited and de novo copy number variants as well as common SNPs. We will use next generation sequencing technology to obtain whole genome DNA sequence for 400 samples. Aim 1: From among the >18,000 samples for whom we have GWAS data we will select SCZ and BPD patients from a Swedish sample, enriched for family- history of disease, for whom we have matched controls, and from a US sample enriched for sporadic cases, for whom parental DNA samples are available. Perform whole genome sequencing to identify DNA variation. Aim 2: Develop an analytic framework to annotate, curate and query the genetic data with respect to disease status. Aim 3: Follow-up sequencing results, including in silico genotyping, deep sequencing of targeted regions in 3000 individuals and genotyping specific variants in over 18,000 individuals. All data and software tools will be made available as a resource to the broader community. PUBLIC HEALTH RELEVANCE: Narrative: We will obtain whole genome sequence data using next generation high-throughput technology in patients with schizophrenia and bipolar disorder and matched controls to find new genetic variation that may be associated with these diseases. They are large public health problems affecting millions of Americans and have no effective treatments.