Genetics of PTSD in African Ancestry Populations: Enhancing discovery by addressing inequality

非洲血统人群 PTSD 的遗传学：通过解决不平等问题加强发现

基本信息

批准号：
10750547
负责人：
Dickens Howard Akena
金额：
$ 179.95万
依托单位：
BROAD INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-25 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10750547
关键词：
Acceleration Address Africa African African ancestry Alleles Chromosome Mapping Copy Number Polymorphism Data Data Collection Disease Electronic Health Record Elements Enrollment Ensure Equity European ancestry Freezing Funding Future Generations Genes Genetic Genetic Databases Genetic Markers Genetic Research Genetic study Genome Genomics Goals Haplotypes Individual Inequality Inequity Institution Investments Kenya Linkage Disequilibrium Maps Measures Mental disorders Meta-Analysis National Institute of Mental Health Participant Performance Persons Population Population Heterogeneity Population Programs Post-Traumatic Stress Disorders Psychiatry Recontacts Research Research Personnel Resources Risk Sample Size Sampling Scientific Advances and Accomplishments Signal Transduction Single Nucleotide Polymorphism Strategic Planning Time Trauma Uganda Variant Work biobank causal variant cohort data integration electronic health data gene discovery genetic architecture genetic risk factor genome resource genome wide association study genome-wide genome-wide analysis health inequalities improved large scale data meetings multi-ethnic neuropsychiatry non-genomic novel therapeutics polygenic risk score psychiatric genomics rare variant risk prediction risk variant success treatment disparity working group

项目摘要

PROJECT SUMMARY / ABSTRACT The broad goal of this application is to advance PTSD genetic discovery and address inequity in PTSD genetics research by leveraging a partnership between the Psychiatric Genomics Consortium – Posttraumatic Stress Disorder Working Group (PGC-PTSD) and a network of African investigators, including the Neuropsychiatric Genetics in African Populations (NeuroGAP) program and the Ugandan Genome Resource (UGR). By the end of 2022, the PGC-PTSD will achieve the largest genetic mapping of PTSD to date based on multiethnic meta- analysis of > 1,280,000 samples, leading to 95 risk loci meeting genome-wide significance for PTSD. Beyond discovery, recent work on polygenic risk scores in PTSD shows the potential for the utility of these measures in research. This success is overshadowed, however, by the persistent underrepresentation of African populations in PTSD genetic research, which poses a challenge for both scientific advances in PTSD and global equity. African genomes are characterized by shorter haplotype blocks and contain almost a million more variants per individual than populations outside Africa. The lower correlation between genetic markers in African populations is also useful for fine- mapping disease-causing alleles. However, differences in the African genome also result in limited cross-population transferability of polygenic risk scores, and, by extension, poorer performance in uncharacterized populations such as those from Africa. There is significant risk that the recent advances in PTSD genetics will result in a widening of the massive research and treatment disparities for African populations. This inequity is particularly troubling given the disproportionately high burden of trauma and PTSD faced by African populations both in the US and on the African continent. Thus, data from African populations in genetic studies of PTSD are critical to generate a complete picture of genetic risk factors, identify potentially missing novel therapeutic signals garnered by studying all populations, and address growing health inequity. We propose addressing this inequity by accomplishing the following Specific Aims: (1) Expand the PGC–PTSD sample bank with over 27,000 cases and 112,000 controls from the African continent and diaspora to achieve a robust, well- powered sample size of over 190,000 participants (~39,000 cases, 151,000 controls) with African ancestry; (2) Integrate data across Africa and African diaspora and perform analyses to expand PTSD risk loci discovery; and (3) Leverage African ancestry populations to improve fine-mapping and gene prioritization and to reduce health inequality by improving PRS accuracy for PTSD in these populations. These aims are highly consistent with NIMH Strategic Plan Goal 1, Objective 1.2, Strategy 1.2.A “Discovering gene variances and other genomics elements that contribute to mental illnesses in diverse populations.”

项目概要/摘要该应用程序的总体目标是推进 PTSD 基因发现并解决 PTSD 遗传学中的不平等问题利用精神病基因组学联盟之间的合作伙伴关系进行研究——创伤后应激障碍疾病工作组 (PGC-PTSD) 和非洲研究人员网络，包括神经精神科非洲人口遗传学 (NeuroGAP) 计划和乌干达基因组资源 (UGR)。到 2022 年，PGC-PTSD 将基于多种族元数据实现迄今为止最大的 PTSD 基因图谱对超过 1,280,000 个样本进行分析，得出 95 个符合 PTSD 全基因组显着性的风险位点。发现，最近关于 PTSD 多基因风险评分的研究表明了这些措施在然而，这一成功却因非洲人口代表性持续不足而黯然失色。创伤后应激障碍（PTSD）基因研究，这对创伤后应激障碍（PTSD）的科学进步和全球公平构成了挑战。非洲基因组的特点是单倍型块较短，并且每个基因组包含近一百万个变体非洲人群遗传标记之间的相关性低于非洲以外人群。对于精细绘制致病等位基因图谱也很有用，但是，非洲基因组的差异也会导致这种情况。多基因风险评分的跨人群可转移性有限，并且推而广之，在创伤后应激障碍 (PTSD) 的最新进展存在重大风险。遗传学将导致非洲人口的巨大研究和治疗差异扩大。鉴于非洲人面临着不成比例的沉重创伤和创伤后应激障碍负担，不平等现象尤其令人不安因此，基因研究中的数据来自非洲人口。创伤后应激障碍 (PTSD) 的研究对于全面了解遗传风险因素、识别潜在缺失的新发现至关重要通过研究所有人群获得的治疗信号，并解决日益严重的健康不平等问题。通过实现以下具体目标来解决这种不平等问题： (1) 扩大 PGC-PTSD 样本库来自非洲大陆和侨民的 27,000 多例病例和 112,000 例对照，以实现稳健、良好的样本量超过 190,000 名具有非洲血统的参与者（约 39,000 名病例，151,000 名对照）（2）；整合非洲和非洲侨民的数据并进行分析，以扩大创伤后应激障碍（PTSD）风险位点的发现； (3) 利用非洲血统人群改善精细绘图和基因优先排序并降低健康水平通过提高这些人群中 PTSD 的 PRS 准确性来消除不平等。这些目标与以下内容高度一致。 NIMH 战略计划目标 1、目标 1.2、战略 1.2.A“发现基因变异和其他基因组学导致不同人群精神疾病的因素。”