Genomewide Association & High-Throughput Sequencing of Psychotic Bipolar Disorder

全基因组协会

基本信息

批准号：
8661788
负责人：
Fernando Sampaio Goes
金额：
$ 24.46万
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 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8661788
关键词：
Affect Bioinformatics Bipolar Disorder Bipolar I 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 High-Throughput Nucleotide Sequencing 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 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 next generation sequencing novel proband promoter psychogenetics psychotic symptoms rare variant risk variant segregation suicidal risk

项目摘要

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。