Psychiatric Genomics Consortium for PTSD

创伤后应激障碍 (PTSD) 精神病学基因组学联盟

基本信息

批准号：
9335458
负责人：
KARESTAN C KOENEN
金额：
$ 83.85万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-19 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9335458
关键词：
American Anorexia Nervosa Architecture Attention deficit hyperactivity disorder Autistic Disorder Biological Biological Process Bipolar Disorder Chronic Collaborations Complement Copy Number Polymorphism Country Data Data Set Detection Development Diagnosis Disease Drug Use Disorder Environment Environmental Risk Factor Exposure to Family Family Study Funding Genes Genetic Genetic Risk Genetic Variation Genomic approach Genomics Genotype Gilles de la Tourette syndrome Heritability Individual Institutes Institution Interpersonal Violence Intervention Life Major Depressive Disorder Measures Mental disorders Meta-Analysis Minority Molecular National Institute of Mental Health Neurobiology Numbness Pathway Analysis Pathway interactions Persons Phenotype Post-Traumatic Stress Disorders Prevalence Prevention Psychiatry Recording of previous events Recruitment Activity Research Personnel Risk Risk Factors Sample Size Sampling Schizophrenia Scientist Severities Strategic Planning Symptoms Syndrome Testing Time Trauma Twin Multiple Birth Twin Studies United States National Institutes of Health Variant Work case control cohort disorder risk experience genetic risk factor genetic variant genome wide association study genome-wide genome-wide analysis improved novel pediatric trauma phenotypic data population stratification public health relevance rare variant resilience risk sharing risk variant success symptom cluster traumatic event

项目摘要

DESCRIPTION (provided by applicant): Post-traumatic stress disorder (PTSD) occurs only in vulnerable individuals after exposure to severe traumatic events. This risk is due, in part, to 40-70% heritability of differential vulnerability or resilience. In fact, recent studies have suggeste that the heritability for PTSD may be twice that of Major Depressive Disorder. Due to increasing collaborations across the field of PTSD genomics, it is a very exciting time for discovering the underlying genetic risk factors contributing to PTSD. The purpose of this application is to facilitate meta- analyses of genome-wide association study (GWAS) data for symptoms and diagnosis of PTSD. We propose to conduct this first large-scale meta-analysis through the PTSD group of the Psychiatric Genomics Consortium (PGC). The PGC was created in 2007 to conduct field-wide mega-analyses of individual data for five major psychiatric disorders. It united the field for the first time, and it is the largest consortium (>500 scientists from >80 institutios in 25 countries) in the history of psychiatry. The PGC has already produced three major findings with regard to the genetic architecture of psychiatric disorders. First, reliable associations can be identified with extremely large sample sizes. A meta-analysis of GWAS in SCZ has produced over 100 loci at the genome-wide significance threshold in a sample of 36,000 cases and 43,000 controls. Second, the polygenic architecture inferred from family studies was confirmed with molecular evidence, and refined via demonstration of substantial effects of both common and rare variants. Third, confirming findings from twin studies, there are shared genetic contributions among psychiatric disorders. The PGC-PTSD group was launched in May 2013 and since then has been enormously successful, with over 25 investigators contributing genotype data from over 20 studies with a total N of over 76,000 combined cases and trauma-exposed controls. We also have commitments of collaborations using ~ 77,000 additional cases and controls from banked samples from over 20 studies, and our progress thus far demonstrates feasibility of the proposed work. We hypothesize that with well-powered, large sample-size studies, along with a deeply phenotyped set of cohorts, the PGC-PTSD group can identify the genetic architecture of PTSD. We will test this hypothesis through our Primary Aim focusing on detecting novel genetic variation associated with risk for PTSD. The primary aim of this study is to detect novel genetic variants (SNPs and CNVs) that predict the development of PTSD following trauma. We will conduct the study in three stages - discovery, biological annotation, and replication. This aim will be supplemented by Exploratory Aims which will expand the genomic approaches to include GxE analyses, meta-analyses of intermediate phenotypes, and cross disorder polygenic risk score analyses. Identifying the genetic pathways underlying PTSD will lead to an improved neurobiological understanding, enhanced prevention, and improved treatment of this debilitating and prevalent syndrome.

描述（由适用提供）：创伤后应激障碍（PTSD）仅在暴露于严重创伤事件后脆弱的个体中。这种风险部分归因于差异脆弱性或韧性的40-70％的遗传力。实际上，最近的研究表明，PTSD的遗传力可能是主要抑郁症的两倍。由于PTSD基因组学领域的合作越来越大，这是发现有助于PTSD的潜在遗传危险因素的一个非常激动人心的时刻。该应用的目的是促进全基因组关联研究（GWAS）数据的荟萃分析，以了解PTSD的症状和诊断。我们建议通过精神病学联盟（PGC）的PTSD组进行第一个大规模的荟萃分析。 PGC成立于2007年，旨在为五种主要精神疾病的单个数据进行范围内的大型脉络膜。它团结起来该领域是第一次，它是精神病学史上最大的财团（来自25个国家 /地区> 80个研究所的500个科学家）。 PGC在精神疾病的遗传结构方面已经提出了三个主要发现。首先，可以用极大的样本量来识别可靠的关联。 SCZ中GWAS的荟萃分析在36,000例病例和43,000例对照样本中，在全基因组显着性阈值下产生了100多个基因座。其次，通过分子证据证实了从家庭研究中推断出的多基因结构，并通过证明共同变体和稀有变体的实质作用来进行完善。第三，确认双胞胎研究的发现，精神疾病之间存在共同的遗传贡献。 PGC-PTSD组于2013年5月启动，此后取得了巨大成功，超过25个研究人员从20多个研究中贡献了基因型数据，共有76,000多个合并病例和外伤暴露对照。我们还采用了约77,000例来自20多个研究的银行样本的其他案例和控制的合作承诺，迄今为止，我们的进展证明了拟议工作的可行性。我们假设，通过有力的大型样品大小的研究，以及一组深层的同类群体，PGC-PTSD组可以识别PTSD的遗传结构。我们将通过我们的主要目标来检验这一假设，重点是检测与PTSD风险相关的新遗传变异。这项研究的主要目的是检测创伤后PTSD发展的新型遗传变异（SNP和CNV）。我们将在三个阶段进行研究 - 发现，生物学注释和复制。探索目的将补充该目标，该目标将扩大基因组方法，包括GXE分析，中间表型的荟萃分析以及跨疾病多基因风险评分分析。确定PTSD的遗传途径将导致神经生物学的理解，增强预防，并改善对这种衰弱和流行综合征的治疗。