Genomewide Association & High-Throughput Sequencing of Psychotic Bipolar Disorder

全基因组协会

• 批准号: 8441986
• 负责人: Fernando Sampaio Goes
• 金额: $ 24.9万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-02 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8441986
• 关键词: Affect; Bioinformatics; Bipolar Disorder; Classification; Conserved Sequence; Custom; DNA Sequence; Disease; Drug Design; Epidemiologist; Etiology; Exons; Extended Family; Family; Foundations; Functional disorder; Generations; Genes; Genetic; Genetic Predisposition to Disease; Genome; Goals; Individual; Investigation; Linkage Disequilibrium; Mentors; Mentorship; Molecular; Mood Disorders; Morbidity - disease rate; Mutation; Pathway interactions; Patients; Phase; Phenotype; Population; Postdoctoral Fellow; Potassium Hydroxide; Predisposition; Psychiatrist; Publishing; Relative (related person); Research; Research Personnel; Research Proposals; Risk; Sampling; Schizophrenia; Severities; Severity of illness; Statistical Methods; Structure; Susceptibility Gene; Symptoms; Techniques; Technology; Testing; Training; Trust; Untranslated Regions; Variant; Work; base; case control; disability; drug development; experience; genetic epidemiology; genetic variant; genome wide association study; genome-wide; insight; meetings; member; next generation; novel; proband; promoter; psychogenetics; segregation; suicidal risk

Psychotic symptoms in bipolar disorder (BP) are common, correlate with greater severity of illness, and represent a familial subtype of BP with possible etiological ties to schizophrenia. The long term goal of this K99/R00 application is to uncover susceptibility genes for this serious form of BP. The candidate is a psychiatrist with post-doctoral research experience in mood disorders and genetic epidemiology, who seeks to develop expertise in next-generation DNA sequencing, high-throughput bioinformatics and statistical methods to help uncover the genetic underpinnings of psychotic BP. The primary hypothesis to be tested is that susceptibility genes for psychotic BP will harbor both common and rare causal variants. To test this hypothesis, we propose the following specific aims: (1) To perform a secondary analysis of a BP genome-wide association study (GWAS) using 1200 psychotic BP cases, 900 non-psychotic BP cases and 1500 controls, and to replicate our best findings in a similarly powered independent replication sample. (2) To select genes that meet genome-wide significance in the combined discovery and replication sample and sequence all exons, UTRs, promoters, and highly conserved sequences in 500 cases with psychotic BP and 500 controls using a novel microarray enrichment technique and second generation high-throughput sequencing technology. (3) To validate our findings by performing: a) case-control replication analysis of 1000 additional cases with psychotic BP and 1000 controls; b) selected sequencing of multiply affected families to find evidence of co-segregation between a putative causal variant and disease status. The training and research proposal will enable the candidate to develop into an independent investigator in psychiatric genetics, and has the potential to identify novel susceptibility variants for psychotic BP. Primary mentorship will be provided by Dr. James Potash, director of research for mood disorders at Johns Hopkins, with co-mentorship from Dr. Richard McCombie, co-director of the CSHL Genome Center and an expert in high throughput sequencing and Dr. Peter Zandi, a genetic epidemiologist with expertise in bioinformatics .

双相情感障碍 (BP) 的精神病症状很常见，与严重程度相关 疾病，并代表 BP 的一种家族亚型，其病因可能与精神分裂症有关。 K99/R00 应用的长期目标是发现这种严重疾病的易感基因 BP 的形式。候选人是一名精神科医生，拥有情绪方面的博士后研究经验 疾病和遗传流行病学，致力于发展下一代 DNA 方面的专业知识 测序、高通量生物信息学和统计方法有助于揭示基因 精神病性血压的基础。要检验的主要假设是易感基因 精神病性血压将包含常见和罕见的因果变异。为了检验这个假设，我们 提出以下具体目标：（1）对BP全基因组进行二次分析 关联研究 (GWAS) 使用 1200 例精神病性 BP 病例、900 例非精神病性 BP 病例和 1500 个控制，并在类似动力的独立复制中复制我们的最佳发现 样本。 (2) 在联合发现中选择符合全基因组意义的基因 复制样本并测序所有外显子、UTR、启动子和高度保守的 使用新型微阵列对 500 例精神病性 BP 病例和 500 例对照进行序列分析 富集技术和二代高通量测序技术。 (3) 至 通过执行以下操作来验证我们的发现：a) 对另外 1000 个病例进行病例对照复制分析 患有精神病性血压和 1000 名对照； b) 对多重受影响的家庭进行选定的排序，以发现 假定的因果变异和疾病状态之间共分离的证据。培训内容 研究计划将使候选人能够发展成为一名独立研究者 精神病遗传学，并有可能识别精神病的新易感性变异 血压。主要指导将由情绪研究主任 James Potash 博士提供 约翰·霍普金斯大学的疾病研究中心联合主任理查德·麦康比 (Richard McCombie) 博士共同指导 CSHL 基因组中心和高通量测序专家 Peter Zandi 博士 具有生物信息学专业知识的遗传流行病学家。