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：
9816833
负责人：
KARESTAN C KOENEN
金额：
$ 83.56万
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9816833
关键词：
3-Dimensional Address Amygdaloid structure Architecture Bayesian Method Behavior Biological Biological Sciences Brain Clinical Collaborations Comorbidity Complex Copy Number Polymorphism Country Data Data Collection Data Set Detection Development Diagnosis Disease Ensure Epigenetic Process Etiology Evaluation Exposure to Family Study Female Foundations Frequencies Fright Future Genes Genetic Genetic Diseases Genetic Risk Genetic Variation Genetic study Genomics Genotype Goals Heritability Hippocampus (Brain)Human Genetics Individual International Knowledge Measures Mental Depression Mental disorders Meta-Analysis Modeling Molecular National Institute of Mental Health Neurobiology Pathway interactions Peripheral Persons Phenotype Post-Traumatic Stress Disorders Prevention Psychiatry Psychometrics Randomized Recording of previous events Research Research Domain Criteria Research Personnel Research Priority Risk Sample Size Sampling Schizophrenia Scientist Shapes Signal Transduction Solid Source Strategic Planning Symptoms Syndrome Testing Therapeutic Time Tissues Trauma Twin Studies United States National Institutes of Health Untranslated RNA Validation Variant Veterans Work analytical tool base brain volume causal variant epigenetic variation genetic architecture genetic variant genome wide association study genome-wide high risk improved insight novel phenotypic data protective factors protein protein interaction resilience response risk variant success symptom cluster tool trait transcriptomics trauma exposure traumatic event working group

项目摘要

Project Summary Psychiatric Genomics Consortium for PTSD Posttraumatic stress disorder (PTSD) occurs only in vulnerable individuals after exposure to severe traumatic events. This risk is due, in part, to 40-50% heritability of differential vulnerability. Due to increasing collaborations across the field of PTSD genomics and the advent of new analytical tools, it is a very exciting time for PTSD genetic risk discovery. 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 large-scale meta-analyses 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 5 major psychiatric disorders. With its current 11 working groups, it is the largest consortium (>800 scientists from 40 countries) in the history of psychiatry. The PGC has produced major findings with regard to the genetic architecture of psychiatric disorders. Meta-analyses of GWAS have produced over 100 loci at the genome- wide significance threshold, at sample sizes ranging from 36,000 cases for schizophrenia to 246K cases for depression. The polygenic architecture inferred from family studies was confirmed with molecular evidence. Corroborating findings from twin studies, shared genetic contributions among psychiatric disorders has been found. The PGC-PTSD group was launched in 2013 and has been enormously successful. Currently our multi- ethnic data collection includes genotypes from 60 studies with a total N of over 200K combined cases and trauma-exposed controls. We recently identified 6 genome-wide significant loci and generated a polygenic risk score to identify individuals at highest risk for PTSD after trauma exposure. We hypothesize that with an increased sample size and deeper phenotype characterization, the PGC- PTSD will accelerate our current understanding of the genetic architecture of PTSD. Our progress thus far demonstrates feasibility and initial successes of the proposed work. Aim 1 will increase sample size (with commitments for 50K additional cases and 300K controls from banked samples) to reach the PGC goal of 100K cases for psychiatric disorders, create psychometrically optimized PTSD subphenotypes, conduct GWAS meta-analyses to detect novel common variants, and identify copy-number variants (CNVs) hypothesized to contribute to PTSD heritability through rare and low-frequency CNVs. This aim will be supplemented by the contribution of diverse ancestry groups to ensure that advances in our genetic understanding of PTSD extend across ancestral backgrounds in Aim 2. Aim 3 is centered around the characterization of functional consequences of identified variants. Lastly, we will use polygenic risk scores (PRS) to provide insights into relationships to other traits and advance causal inference in Aim 4. Identifying the genetic pathways underlying PTSD will lead to improved neurobiological understanding, enhanced prevention, and improved treatment of this debilitating and prevalent syndrome.

项目概要创伤后应激障碍 (PTSD) 精神病学基因组学联盟创伤后应激障碍 (PTSD) 仅发生在暴露于严重环境之后的脆弱个体中。创伤性事件。这种风险部分归因于差异脆弱性的 40-50% 遗传力。由于增加 PTSD 基因组学领域的合作以及新分析工具的出现，这是一个非常令人兴奋的事情是时候发现 PTSD 遗传风险了。该应用程序的目的是促进基因组的荟萃分析 PTSD 症状和诊断的广泛关联研究 (GWAS) 数据。我们建议通过精神病基因组学的 PTSD 小组进行大规模荟萃分析财团（PGC）。 PGC 成立于 2007 年，旨在对 5 个领域的个人数据进行全领域大型分析主要精神疾病。目前拥有 11 个工作组，是最大的联盟（超过 800 名科学家）来自 40 个国家）精神病学史上。 PGC 在遗传方面取得了重大发现精神疾病的结构。 GWAS 的荟萃分析已经在基因组中产生了 100 多个位点显着性阈值较宽，样本量范围从精神分裂症的 36,000 例到精神分裂症的 246,000 例沮丧。从家族研究中推断出的多基因结构得到了分子证据的证实。双胞胎研究证实了精神疾病之间的共同遗传贡献成立。 PGC-PTSD 小组于 2013 年成立，并取得了巨大成功。目前我们的多种族数据收集包括来自 60 项研究的基因型，总病例数超过 20 万个暴露于创伤的对照。我们最近鉴定了 6 个全基因组重要位点并产生了多基因风险评分来识别遭受创伤后患 PTSD 风险最高的个体。我们假设随着样本量的增加和表型表征的深入，PGC- PTSD 将加速我们目前对 PTSD 遗传结构的理解。迄今为止我们的进展展示了拟议工作的可行性和初步成功。目标 1 将增加样本量（承诺增加 5 万个病例和来自银行样本的 30 万个对照），以实现 PGC 的目标 10 万例精神疾病病例，创建心理测量优化的 PTSD 亚表型，进行 GWAS 荟萃分析以检测新的常见变异，并识别假设的拷贝数变异（CNV）通过罕见和低频的 CNV 促进 PTSD 遗传。这一目标将得到补充不同血统群体的贡献，以确保我们对 PTSD 的遗传理解的进步能够扩展目标 2 中跨越祖先背景。目标 3 围绕功能特征的表征已识别变体的后果。最后，我们将使用多基因风险评分（PRS）来深入了解与其他性状的关系并推进目标 4 中的因果推断。确定潜在的遗传途径 PTSD 将提高神经生物学的理解、加强预防和改善治疗这种使人衰弱且普遍的综合症。