Genomewide Association & High-Throughput Sequencing of Psychotic Bipolar Disorder

全基因组协会

基本信息

批准号：
8523972
负责人：
Fernando Sampaio Goes
金额：
$ 23.9万
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 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8523972
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 next generation sequencing novel proband promoter psychogenetics 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 .

躁郁症（BP）中的精神病症状很常见，与更严重的程度相关疾病，代表BP的家族性亚型，可能与精神分裂症有关。该K99/R00应用的长期目标是发现这种严重的敏感性基因 BP的形式。候选人是一名精神科医生，具有情绪后研究经验疾病和遗传流行病学，他们试图发展下一代DNA的专业知识测序，高通量生物信息学和统计方法，以帮助发现遗传精神病基础的基础。要测试的主要假设是敏感性基因对于精神病，BP将具有常见和罕见的因果变体。为了检验这一假设，我们提出以下特定目的：（1）对BP基因组进行辅助分析协会研究（GWAS）使用1200个精神病BP病例，900例非精神病BP病例和 1500个控件，并在类似的独立复制中复制我们的最佳发现样本。（2）选择在共同发现中符合全基因组重要性的基因和复制样本和序列所有外显子，UTR，启动子和高度保守使用新型微阵列的500例精神病和500个对照的序列富集技术和第二代高通量测序技术。（3）到通过执行验证我们的发现：a）对1000例其他情况的情况对照复制分析具有精神病性BP和1000个对照； b）选定的乘影响家庭的测序以找到假定的因果变异和疾病状况之间共隔离的证据。培训研究建议将使候选人能够发展成独立的研究者精神病遗传学，并有潜力识别精神病的新型易感性变体 bp。主要指导将由情绪研究总监James Potash博士提供约翰·霍普金斯（Johns Hopkins）的疾病，由Richard McCombie博士的联合主任， CSHL基因组中心和高通量测序的专家和彼得·赞迪（Peter Zandi）博士具有生物信息学专业知识的遗传流行病学家。