Genomewide Association & High-Throughput Sequencing of Psychotic Bipolar Disorder

双相情感障碍(BP)的精神症状是常见的，与更严重的 疾病，代表了BP的一种家族亚型，可能与精神分裂症的病因有关。 这项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。这位候选人是一名精神病学家，拥有心境方面的博士后研究经验 疾病和遗传流行病学，世卫组织寻求开发下一代DNA的专业知识 测序，高通量生物信息学和统计方法，以帮助揭示基因 精神病BP的基础。需要检验的主要假设是易感基因 对于精神病患者来说，BP既有常见的因果变异，也有罕见的因果变异。为了检验这一假设，我们 提出以下具体目标：(1)对全基因组的BP进行二次分析 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，并在类似功率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 并对所有外显子、UTRs、启动子和高度保守的 应用新型基因芯片对500例精神病性BP患者和500例对照进行测序 浓缩技术和第二代高通量测序技术。(3)至 通过以下方式验证我们的发现：a)对另外1000例病例进行病例对照重复分析 患有精神病的BP和1000名对照；b)对多个受影响的家庭进行精选测序以找到 推定的因果变异和疾病状态之间存在共分离的证据。培训 和研究方案将使候选人发展成为一名独立的调查员在 精神病学遗传学，并有可能识别精神病的新易感变异 BP。初级指导将由Mod研究主管James Potash博士提供 约翰霍普金斯大学的精神障碍，由理查德·麦康比博士共同指导，该中心的联合主任 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。

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 .