Genetic Determinants of Schizophrenia Intermediate Phenotypes

精神分裂症中间表型的遗传决定因素

基本信息

批准号：
8909190
负责人：
Tracey Petryshen
金额：
$ 39.67万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-10 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8909190
关键词：
Address Architecture Attention Base of the Brain Brain Brain imaging Candidate Disease Gene Clinical Cognition Cognitive Cognitive deficits Collection Consensus DNA Data Data Analyses Data Set Development Disease Early Intervention Early treatment Functional disorder Funding Genetic Genetic Determinism Genetic Predisposition to Disease Genetic Research Genetic Variation Genome Genotype Grant Image Impaired cognition Impairment International Intervention Investigation Knowledge Language Lead Link Measures Memory Meta-Analysis Neurobiology Neurocognition Outcome Outcomes Research Patients Pharmaceutical Preparations Phenotype Predisposition Process Public Health Regression Analysis Research Research Personnel Resolution Risk Risk Factors Role Sampling Schizophrenia Seminal Short-Term Memory Structure Testing Therapeutic Translating United States National Institutes of Health Variant Verbal Learning Visuospatial Weight Work cognitive function daily functioning effective therapy gene function genetic variant genome wide association study genome-wide genotyping technology gray matter improved insight neural correlate neuroimaging neuromechanism outcome forecast patient population pleiotropism processing speed relating to nervous system risk variant sample collection trait vigilance white matter

Address Architecture Attention Base of the Brain Brain Brain imaging Candidate Disease Gene Clinical Cognition Cognitive Cognitive deficits Collection Consensus DNA Data Data Analyses Data Set Development Disease Early Intervention Early treatment Functional disorder Funding Genetic Genetic Determinism Genetic Predisposition to Disease Genetic Research Genetic Variation Genome Genotype Grant Image Impaired cognition Impairment International Intervention Investigation Knowledge Language Lead Link Measures Memory Meta-Analysis Neurobiology Neurocognition Outcome Outcomes Research Patients Pharmaceutical Preparations Phenotype Predisposition Process Public Health Regression Analysis Research Research Personnel Resolution Risk Risk Factors Role Sampling Schizophrenia Seminal Short-Term Memory Structure Testing Therapeutic Translating United States National Institutes of Health Variant Verbal Learning Visuospatial Weight Work cognitive function daily functioning effective therapy gene function genetic variant genome wide association study genome-wide genotyping technology gray matter improved insight neural correlate neuroimaging neuromechanism outcome forecast patient population pleiotropism processing speed relating to nervous system risk variant sample collection trait vigilance white matter

展开

项目摘要

DESCRIPTION (provided by applicant): Schizophrenia (SCZ) is a devastating illness characterized by severe impairments in neurocognition and brain function. Cognitive deficits seriously impair daily functioning and patient outcome, and are not improved by current medications. The fundamental neural mechanisms underlying the cognitive and brain function impairments are essentially unknown, which is a critical barrier to progress in developing effective treatments and early interventions to improve prognosis. This application proposes to address this problem by contributing knowledge of the genetic causes of brain dysfunction in SCZ. Until recently, SCZ genetic research has been obstructed by poorly phenotyped and underpowered patient populations, and limited genotyping technologies. This application proposes to harness the power and enormous effort of recent genome-wide association studies (GWAS) of SCZ that collectively examined over 50,000 SCZ and control subjects, and conclusively identified sequence variants throughout the genome that confer increased risk of SCZ. While providing invaluable data on the genetic architecture of SCZ, the majority of existing GWAS samples has sparse clinical and phenotypic data that limit their utility in delineating the disease relevance of these risk variants. The research proposed here will investigate the established SCZ risk variants and polygenic risk factors identified by prior GWAS to identify associations with neural correlates of intermediate phenotypes. This investigation will be bolstered by a large collection of 6,400 SCZ and control subjects with extensive phenotypic data available only to the Investigators on this application. The sample collection contains extensive data assessing attention, working memory, and other cognitive domains that are impaired in SCZ, as well as structural imaging data assessing brain structural features. Furthermore, genome-wide SNP data are available for over half of the subjects, and the remaining subjects have DNA available for genotyping. Nearly all of the data utilized by this project are already collected and available to the investigators. Subject recruitment, collection of phenotypic data and DNA, and genome-wide SNP data, as well as GWAS meta- analyses that identified the SCZ risk variants we will examine, were all funded under other NIH grants or by other agencies. The funds requested in this application for nominal genotyping and data analysis are negligible in comparison to these previous efforts, yet will exponentially build upon and add enormous value to those efforts. Our plan to seize upon seminal new findings in the SCZ genetics field is expected to obtain critical insight into the genetic underpinnings of neural dysfunctions at the core of SCZ pathophysiology.

描述（由申请人提供）：精神分裂症（SCZ）是一种毁灭性疾病，其特征是神经认知和脑功能严重损害。认知缺陷严重损害了日常功能和患者的结果，并且没有通过当前的药物改善。认知和脑功能障碍的基本神经机制本质上是未知的，这是开发有效治疗和早期干预措施以改善预后的关键障碍。该应用建议通过了解SCZ中脑功能障碍的遗传原因来解决此问题。直到最近，SCZ遗传研究一直受到表现不佳和功能不足的患者人群以及有限的基因分型技术阻碍。该应用提出了旨在利用SCZ的最新基因组关联研究（GWAS）的力量和巨大努力，该研究共同检查了超过50,000个SCZ和对照对象，并最终确定了整个基因组中赋予SCZ风险增加的序列变体。尽管提供有关SCZ遗传结构的宝贵数据，但大多数现有的GWAS样品具有稀疏的临床和表型数据，这些数据限制了它们在描述这些风险变异的疾病相关性方面的效用。此处提出的研究将调查先前GWAS确定的已建立的SCZ风险变异和多基因风险因素，以鉴定与中间表型的神经相关性的关联。这项调查将由大量的6,400个SCZ和控制受试者加强，并提供广泛的表型数据，仅可供研究人员使用该应用程序。样本收集包含广泛的数据，可评估SCZ中受损的注意力，工作记忆和其他认知领域，以及评估大脑结构特征的结构成像数据。此外，全基因组SNP数据可用于超过一半的受试者，其余受试者具有可用于基因分型的DNA。该项目使用的几乎所有数据都已经收集并提供给研究人员。受试者募集，表型数据和DNA的收集以及全基因组SNP数据以及GWAS Meta-Analyzz识别我们将要检查的SCZ风险变体的GWAS Meta-Analyzz，都是在其他NIH赠款或其他机构下资助的。与以前的努力相比，本申请中要求的用于标称基因分型和数据分析的资金可以忽略不计，但会呈指数级的基础并为这些努力增加巨大的价值。我们有望在SCZ遗传学领域抓住开创性的新发现的计划，将获得对SCZ病理生理学核心神经功能障碍的遗传基础的关键见解。