Identifying Schizophrenia Risk Loci in the MHC Using Next Generation Sequencing

使用下一代测序识别 MHC 中的精神分裂症风险位点

• 批准号: 8568113
• 负责人: Semanti Mukherjee
• 金额: $ 9万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8568113
• 关键词: 6p21; Algorithms; Alleles; Ashkenazim; Autoimmune Process; Automobile Driving; Biological; Biology; Brain; Chromosomes; Cognitive; Complex; Computational Biology; Computer Simulation; Computing Methodologies; Data; Data Set; Databases; Detection; Development; Diagnosis; Disease; Etiology; Founder Generation; Functional disorder; Genes; Genetic; Genetic Heterogeneity; Genetic Variation; Genome; Genomic Segment; Genomics; Genotype; Goals; Grant; Haplotypes; Hereditary Disease; Heritability; Hospitals; Immune; Immune System and Related Disorders; Infection; Inflammatory; Knowledge; Lead; Link; Linkage Disequilibrium; Location; Major Histocompatibility Complex; Mentors; Mentorship; Methods; Mutation; National Institute of Mental Health; Outcome; Pattern; Phase; Population; Population Control; Population Heterogeneity; Predisposition; Prevalence; Property; Publications; Research; Research Personnel; Research Project Grants; Resources; Risk; Role; Sampling; Schizophrenia; Signal Transduction; Source; Staging; Statistical Methods; Technology; Testing; Training; Uncertainty; Universities; Variant; base; case control; cohort; disability; endophenotype; exome; follow-up; follower of religion Jewish; functional genomics; genetic association; genetic risk factor; genome sequencing; genome wide association study; neuropsychiatry; next generation sequencing; novel; novel strategies; prenatal; psychogenetics; public health relevance; repository; risk variant; success

DESCRIPTION (provided by applicant): The goal of this proposed K99/R00 application is to prepare Dr. Semanti Mukherjee to become an independent investigator in psychiatric genetics and computational biology. The primary training objectives are: 1) to expand the applicant's background knowledge in etiology, pathophysiology, and treatment of neuropsychiatric disease, with a major goal of appreciating the role of endophenotypes in explicating disease genetics; and 2) gain theoretical and computational training to develop methods to organize and interpret the complex patterns of rare and novel mutations discovered by next generation sequencing. These training objectives are specifically planned to support two planned research projects. Initially, emphasis will be on development of novel approaches to analyze existing datasets collected by my mentors, particularly Drs. Todd Lencz and Anil Malhotra of Zucker Hillside Hospital. Additional training in computational genomics will be provided by Dr. Itsik Pe'er of Columbia University. In the R00 phase, increased focus is placed upon generating targeted next- generation sequencing and genotype data for more comprehensive analyses. The novel analytic methods I will develop with Dr. Pe'er, as well as the results emerging from these projects, will serve as a rich source of preliminary data to apply for an R01 grant to conduct complex analyses involving large-scale whole genome sequencing datasets that will become available over the next several years. In both components of the Research plan, aims are focused on explicating the role of the major histocompatibility complex (MHC) in schizophrenia. While schizophrenia is a genetically complex disease, the strongest genetic signal observed to date spans the MHC, but precise localization and functional characterization has been impossible due to unique properties of the region. Importantly, the MHC signal supports the well-establish observation of increased risk of SZ associated with prenatal infection and co- occurrence with autoimmune/inflammatory disorders. Hence clarification of role of MHC genetic variation in SZ etiology promises to open new avenues for pathophysiological and treatment research. Research will be primarily performed in our unique Ashkenazi Jewish (AJ) case-control cohort, drawn from a founder population, which can serve to dramatically reduce genetic heterogeneity at the MHC locus. We will also make use of the resources of the Ashkenazi Genome Consortium, which has pioneered the use of whole genome sequencing in this population. Project deliverables will include not only novel genetic association data, including SNP data, haplotype data, and next-generation sequencing data, but also novel analytic algorithms for enhanced interrogation of these datasets.

描述（由申请人提供）：该提出的K99/R00应用程序的目的是准备Semanti Mukherjee博士成为精神遗传学和计算生物学的独立研究者。主要的培训目标是：1）扩大申请人在病因，病理生理学和神经精神疾病的治疗方面的背景知识，其主要目标是欣赏内跨表型在阐明疾病遗传学中的作用； 2）获得理论和计算训练，以开发方法来组织和解释下一代测序发现的稀有和新型突变的复杂模式。这些培训目标是专门计划支持两个计划的研究项目的。最初，重点将放在开发新方法，以分析我的导师，尤其是DRS收集的现有数据集。扎克山区医院的托德·兰兹（Todd Lencz）和阿尼尔·马尔霍特拉（Anil Malhotra）。哥伦比亚大学的Itsik Pe'er博士将提供有关计算基因组学的额外培训。在R00阶段，增加的重点是生成针对性的下一代测序和基因型数据以进行更全面的分析。我将与Pe'er博士一起开发的新型分析方法以及这些项目中出现的结果，将作为富含初步数据的来源，以申请R01赠款，以进行涉及大规模整个基因组测序的复杂分析在未来几年内将可用的数据集。在研究计划的两个组成部分中，目标都集中在阐明主要组织相容性复合物（MHC）在精神分裂症中的作用。虽然精神分裂症是一种遗传复杂的疾病，但迄今为止观察到的最强的遗传信号跨越了MHC，但是由于该地区的独特特性，精确的定位和功能表征是不可能的。重要的是，MHC信号支持对与产前感染和与自身免疫性/炎症性疾病共同发生的SZ风险增加的良好观察。因此，澄清MHC遗传变异在SZ病因中的作用有望为病理生理和治疗研究开辟新的途径。研究将主要是在我们独特的Ashkenazi犹太人（AJ）案例对照组中进行的，该案例对照人群是由创始人人口绘制而来的，这些人群可以大大降低MHC基因座的遗传异质性。我们还将利用Ashkenazi基因组联盟的资源，该联盟率先在该人群中使用了整个基因组测序。项目可交付成果不仅包括新的遗传关联数据，包括SNP数据，单倍型数据和下一代测序数据，还包括用于增强这些数据集询问的新型分析算法。