Genomewide Association & High-Throughput Sequencing of Psychotic Bipolar Disorder

双相情感障碍（BP）的精神病性症状很常见，与更严重的 疾病，并代表一个家族亚型的BP与精神分裂症的可能病因联系。 这项K99/R00应用的长期目标是揭示这种严重疾病的易感基因。 BP的形式。候选人为精神科医生，有心境博士后研究经验 疾病和遗传流行病学，谁寻求发展下一代DNA的专业知识， 测序，高通量生物信息学和统计方法，以帮助揭示遗传 精神病性BP的基础待检验的主要假设是易感基因 对于精神病性BP来说，既有常见的，也有罕见的致病变异。为了验证这个假设，我们 提出以下具体目标：（1）对BP全基因组进行二级分析 使用1200例精神病性BP病例、900例非精神病性BP病例和1200例非精神病性BP病例进行关联研究（GWAS）。 1500个控制，并在类似的动力独立复制中复制我们的最佳发现 sample. (2)选择在联合发现中符合全基因组意义的基因 和复制样品和序列的所有外显子，UTR，启动子，和高度保守的 500例精神病性BP患者和500例对照者使用一种新的微阵列 富集技术和第二代高通量测序技术。(3)到 通过以下方式验证我们的发现：a）对1000例额外病例进行病例对照复制分析 B）选择性地对多个受影响的家庭进行测序，以发现 假定的致病变异和疾病状态之间的共分离的证据。培训 和研究建议将使候选人发展成为一个独立的调查员， 精神病遗传学，并有可能确定新的易感性变异的精神病 BP.主要导师将由情绪研究主任詹姆斯·波塔什博士提供 疾病在约翰霍普金斯，与共同导师博士理查德麦康比，共同主任的 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 .