Genomewide Association & High-Throughput Sequencing of Psychotic Bipolar Disorder

全基因组协会

基本信息

批准号：
7787441
负责人：
Fernando Sampaio Goes
金额：
$ 15.06万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-02 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7787441
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 public health relevance segregation suicidal risk

项目摘要

DESCRIPTION (provided by applicant): 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 . PUBLIC HEALTH RELEVANCE: Project Narrative Bipolar disorder type I affects 1% of the U.S. population and is one of the top ten worldwide causes of disability. Psychotic symptoms occur in approximately half of all patients with bipolar disorder and correlate with increased illness severity and, possibly, increased risk of suicide. Although psychotic bipolar disorder is heritable and clusters within families, little is known about its underlying genetic etiology. This work proposed to uncover gene(s) associated with susceptibility to psychotic Bipolar Disorder, which should provide insights into the pathophysiology of the disorder, and may point to targets appropriate for rational drug development.

描述（由申请人提供）：双相情感障碍 (BP) 的精神病症状很常见，与疾病的严重程度相关，并且代表 BP 的家族亚型，可能与精神分裂症有病因联系。 K99/R00 应用的长期目标是发现这种严重 BP 的易感基因。该候选人是一位精神病学家，在情绪障碍和遗传流行病学方面拥有博士后研究经验，致力于发展下一代 DNA 测序、高通量生物信息学和统计方法方面的专业知识，以帮助揭示精神病性 BP 的遗传基础。要测试的主要假设是精神病性血压的易感基因将包含常见和罕见的因果变异。为了检验这一假设，我们提出以下具体目标：（1）使用 1200 例精神病性 BP 病例、900 例非精神病性 BP 病例和 1500 例对照对 BP 全基因组关联研究 (GWAS) 进行二次分析，并复制我们在类似动力的独立复制样本中的最佳发现。 (2) 使用新型微阵列富集技术和第二代技术，在发现和复制组合样本中选择符合全基因组显着性的基因，并对 500 例精神病性 BP 病例和 500 例对照的所有外显子、UTR、启动子和高度保守序列进行测序高通量测序技术。 (3) 通过执行以下操作来验证我们的发现：a) 对另外 1000 例精神病性 BP 病例和 1000 例对照进行病例对照复制分析； b) 对多重受影响的家庭进行选择性测序，以寻找假定的因果变异与疾病状态之间共分离的证据。培训和研究计划将使候选人能够发展成为精神遗传学的独立研究者，并有可能识别精神病性血压的新易感性变异。主要指导将由约翰·霍普金斯大学情绪障碍研究主任 James Potash 博士提供，并由 CSHL 基因组中心联合主任、高通量测序专家 Richard McCombie 博士和 Peter 博士共同指导。 Zandi，一位具有生物信息学专业知识的遗传流行病学家。公共卫生相关性：项目叙事 I 型双相情感障碍影响着 1% 的美国人口，是全球十大致残原因之一。大约一半的双相情感障碍患者会出现精神病症状，并且与疾病严重程度的增加以及自杀风险的增加相关。尽管精神病性双相情感障碍是可遗传的并且在家庭中聚集，但对其潜在的遗传病因知之甚少。这项工作旨在揭示与精神病性双相情感障碍易感性相关的基因，这应该为该疾病的病理生理学提供见解，并可能为合理的药物开发指明合适的目标。