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：
10426169
负责人：
KARESTAN C KOENEN
金额：
$ 69.84万
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/10426169
关键词：
3-Dimensional Address Amygdaloid structure Architecture Bayesian Method Behavior Biological Biological Sciences Brain Clinical Collaborations 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 Genetic Genetic Diseases Genetic Risk Genetic Variation Genetic study Genomics Genotype Goals Hereditary Disease Heritability Hippocampus (Brain)Human Genetics Individual International Knowledge Measures Mendelian randomization 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 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 comorbidity epigenetic variation gene network genetic architecture genetic variant genome wide association study genome-wide high risk improved insight multi-ethnic novel phenotypic data polygenic risk score protective factors protein protein interaction psychiatric genomics resilience response risk prediction 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.

项目摘要 PTSD的精神病基因组学联盟创伤后应激障碍（PTSD）仅在暴露于严重的人后才发生创伤事件。这种风险部分归因于差异脆弱性的40-50％的遗传力。由于增加 PTSD基因组学领域的合作以及新的分析工具的出现，这是一个非常令人兴奋的 PTSD遗传风险发现的时间。该应用的目的是促进基因组的荟萃分析广泛的关联研究（GWAS）数据，用于PTSD的症状和诊断。我们建议通过精神病学基因组学的PTSD组进行大规模的荟萃分析财团（PGC）。 PGC成立于2007年，以进行5个单个数据的范围内的大型分析5 主要的精神疾病。凭借目前的11个工作组，它是最大的财团（> 800位科学家来自40个国家 /地区的精神病学史。 PGC对遗传产生了重大发现精神疾病的建筑。 GWA的荟萃分析在基因组中产生了100多个基因座较大的显着性阈值，在36,000例精神分裂症病例到246K病例的样本量范围内沮丧。通过分子证据证实了从家庭研究中推断出的多基因结构。从双胞胎研究中证实发现，精神疾病之间的共同遗传贡献一直是成立。 PGC-PTSD集团于2013年启动，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n超过200k的案例和暴露于创伤的对照。我们最近确定了6个基因组的显着基因座，并产生了多基因风险得分以识别创伤暴露后PTSD风险最高的个体。我们假设随着样本量增加和更深的表型表征，PGC- PTSD将加速我们当前对PTSD遗传结构的理解。到目前为止我们的进步证明了拟议工作的可行性和最初的成功。 AIM 1将增加样本量（随着对50k额外案件的承诺和来自银行样本的30万个控制的承诺），以达到PGC目标精神疾病的100K病例，创建心理优化的PTSD子表型，进行GWAS 荟萃分析可检测新的常见变体，并识别假设的拷贝数变体（CNV）通过稀有和低频CNV促进PTSD遗传力。这个目标将由各种祖先的贡献，以确保我们对PTSD的遗传理解的进步扩展 AIM 2中的跨祖先背景。AIM3以功能的特征为中心确定变体的后果。最后，我们将使用多基因风险分数（PR）来提供见解与其他特征的关系并推进目标4的因果推断。确定遗传途径 PTSD将导致改善神经生物学理解，增强预防以及改善的治疗这种衰弱和普遍的综合征。