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: 8725739
• 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 2014-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8725739
• 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; rare variant; 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）：这个K99/R00申请的目标是使Semanti Mukherjee博士成为精神病学遗传学和计算生物学的独立研究者。主要培养目标是：1)扩展申请人在神经精神疾病的病因学、病理生理学和治疗方面的背景知识，主要目标是了解内表型在解释疾病遗传学中的作用；2)获得理论和计算训练，开发方法来组织和解释由下一代测序发现的罕见和新颖突变的复杂模式。这些培训目标的具体计划是为了支持两个计划中的研究项目。最初，重点将放在开发新的方法来分析我的导师，特别是博士收集的现有数据集。祖克山边医院的托德·伦茨和阿尼尔·马尔霍特拉。哥伦比亚大学的Itsik Pe'er博士将提供计算基因组学方面的额外培训。在R00阶段，增加的重点放在产生有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博士共同开发的新颖分析方法，以及这些项目的结果，将作为申请R01拨款的丰富初步数据来源，用于进行涉及大规模全基因组测序数据集的复杂分析，这些数据集将在未来几年内可用。在研究计划的两个组成部分中，目标集中在阐明主要组织相容性复合体（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遗传信号跨越了MHC，但由于该区域的独特性质，精确定位和功能表征是不可能的。重要的是，MHC信号支持了SZ风险增加与产前感染和自身免疫性/炎症性疾病共同发生的观察结果。因此，阐明MHC遗传变异在SZ病因学中的作用有望为病理生理和治疗研究开辟新的途径。研究将主要在我们独特的阿什肯纳兹犹太人（AJ）病例对照队列中进行，该队列来自创始人群，可以显著减少MHC位点的遗传异质性。我们还将利用阿什肯纳兹基因组联盟的资源，该联盟率先在该人群中使用全基因组测序。项目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的新型分析算法。