Genomewide Association & High-Throughput Sequencing of Psychotic Bipolar Disorder

描述（由申请人提供）：双相情感障碍（BP）中的精神病性症状很常见，与疾病的严重程度相关，代表了BP的家族亚型，可能与精神分裂症有病因联系。这种K99/R00应用的长期目标是发现这种严重形式的BP的易感基因。该候选人是一名精神病学家，在情绪障碍和遗传流行病学方面具有博士后研究经验，他寻求发展下一代DNA测序，高通量生物信息学和统计方法的专业知识，以帮助揭示精神病BP的遗传基础。待检验的主要假设是，精神病性BP的易感基因将包含常见和罕见的因果变异。为了验证这一假设，我们提出了以下具体目标：（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，并在相似功效的独立重复样本中复制我们的最佳结果。(2)选择在联合发现和复制样本中符合全基因组意义的基因，并使用新型微阵列富集技术和第二代高通量测序技术对500例精神病性BP患者和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。(3)为了验证我们的研究结果，进行：a）病例对照重复分析的1000例精神病性BP和1000名对照; B）选择性测序的多重影响的家庭，以寻找证据之间的共分离的一个假定的因果变异和疾病状态。培训和研究计划将使候选人能够发展成为精神病遗传学的独立研究者，并有可能确定精神病BP的新易感性变体。约翰霍普金斯大学情绪障碍研究主任James Potash博士将提供主要指导，CSHL基因组中心联合主任、高通量测序专家Richard McCombie博士和具有生物信息学专业知识的遗传流行病学家Peter Zandi博士将提供共同指导。 公共卫生相关性： I型双相情感障碍影响1%的美国人口，是全球十大残疾原因之一。精神病性症状发生在所有双相情感障碍患者中的大约一半，并且与疾病严重程度的增加以及可能的自杀风险增加相关。虽然精神病性双相情感障碍是遗传性的，并在家庭内集群，很少有人知道其潜在的遗传病因。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，这将为该疾病的病理生理学提供见解，并可能指向适合合理药物开发的靶点。

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.