Genomewide Association & High-Throughput Sequencing of Psychotic Bipolar Disorder

全基因组协会

基本信息

批准号：
8019618
负责人：
Fernando Sampaio Goes
金额：
$ 15.23万
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/8019618
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）：躁郁症（BP）中的精神病症状很常见，与疾病的严重程度更高，代表BP的家族性亚型，可能与精神分裂症有关。此K99/R00应用的长期目标是发现这种严重形式的BP的敏感基因。该候选人是一名精神科医生，具有情绪障碍和遗传流行病学方面的博士后研究经验，他们试图在下一代DNA测序，高通量生物信息方面和统计方法方面发展专业知识，以帮助揭示精神病的遗传上的遗传上的精神病遗传。要测试的主要假设是，精神病BP的易感基因将具有常见和罕见的因果变异。为了检验这一假设，我们提出了以下特定目的：（1）使用1200个精神病性BP病例，900个非精神病性BP病例和1500个对照对BP基因组关联研究（GWAS）进行次要分析，并在类似动力的独立复制样本中复制我们的最佳发现。（2）选择在500例具有精神病性BP和500个对照的病例中，使用新型的微阵列富集技术和第二代高通量测序技术的500例中，所有外显子，UTR，启动子和高度保守的序列都可以在共同发现和复制样本和序列中符合全基因组显着性的基因。（3）通过执行：a）对1000例精神病BP和1000个对照的其他病例的病例对照复制分析验证我们的发现； 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。培训和研究建议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BP的新型敏感性变体。 Johns Hopkins的情绪障碍研究主任James Potash博士将提供主要指导，并由CSHL基因组中心的联合主任Richard McCombie博士，高通量测序的专家Peter Zandi博士，一名在BioInformatics中专业知识的遗传学家Peter Zandi博士。公共卫生相关性：项目叙事躁郁症I类型会影响美国人口的1％，并且是全球十大残疾原因之一。在所有躁郁症患者中，大约一半发生了精神病症状，并且与疾病严重程度的增加相关，并可能增加自杀风险。尽管精神病性躁郁症是可以遗传的，并且在家庭中群中簇，但对其潜在的遗传病因却一无所知。这项工作建议揭示与精神病性躁郁症易感性相关的基因，该基因应提供对该疾病的病理生理学的见解，并可能指出适合合理药物开发的靶标。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Exonic DNA sequencing of ERBB4 in bipolar disorder.

DOI：
10.1371/journal.pone.0020242
发表时间：
2011
期刊：
PloS one
影响因子：
3.7
作者：
Goes FS;Rongione M;Chen YC;Karchin R;Elhaik E;Bipolar Genome Study;Potash JB
通讯作者：
Potash JB

De novo variation in bipolar disorder.

DOI：
10.1038/s41380-019-0611-1
发表时间：
2021-08
期刊：
MOLECULAR PSYCHIATRY
影响因子：
11
作者：
Goes, Fernando S.;Pirooznia, Mehdi;Tehan, Martin;Zandi, Peter P.;McGrath, John;Wolyniec, Paula;Nestadt, Gerald;Pulver, Ann E.
通讯作者：
Pulver, Ann E.

Genome-wide association of mood-incongruent psychotic bipolar disorder.

DOI：
10.1038/tp.2012.106
发表时间：
2012-10-23
期刊：
Translational psychiatry
影响因子：
6.8
作者：
Goes FS;Hamshere ML;Seifuddin F;Pirooznia M;Belmonte-Mahon P;Breuer R;Schulze T;Nöthen M;Cichon S;Rietschel M;Holmans P;Zandi PP;Bipolar Genome Study (BiGS);Craddock N;Potash JB
通讯作者：
Potash JB