Genomewide Association & High-Throughput Sequencing of Psychotic Bipolar Disorder

描述(由申请人提供)：双相情感障碍(BP)的精神病症状很常见，与更严重的疾病相关，并代表BP的一种家族性亚型，可能与精神分裂症有关。这项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。这位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拥有博士后研究经验，他寻求开发下一代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BP的遗传基础。需要检验的主要假设是，精神病型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)对BP全基因组关联研究(Gwas)进行二次分析，使用1200例精神病BP病例、900例非精神病BP病例和1500名对照，并在类似功率的独立复制样本中复制我们的最佳发现。(2)利用新的微阵列浓缩技术和第二代高通量测序技术，在发现和复制相结合的样本中筛选符合全基因组意义的基因，并对500例精神病BP患者和500例对照的所有外显子、UTRs、启动子和高度保守的序列进行测序。(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BP患者和1000例对照进行病例对照重复分析；b)对多个受影响的家系进行选择性测序，以寻找推测的因果变异和疾病状态之间存在共同分离的证据。培训和研究提案将使候选人能够发展成为精神病学遗传学的独立研究员，并有可能识别精神病BP的新易感变异。主要导师将由约翰·霍普金斯大学情绪障碍研究主任詹姆斯·波塔什博士提供，共同导师包括CSHL基因组中心联席主任、高通量测序专家理查德·麦康比博士和具有生物信息学专业知识的遗传流行病学家彼得·赞迪博士。 公共卫生相关性： 项目简介I型双相情感障碍影响美国1%的人口，是全球十大致残原因之一。精神病症状出现在大约一半的双相情感障碍患者中，并与疾病严重程度的增加和自杀风险的增加相关。虽然精神病性双相情感障碍是可遗传的，并在家庭中聚集，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(S)，这将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.