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

• 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
• 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

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.”

项目摘要 /摘要 该应用的广泛目标是提高PTSD遗传发现并解决PTSD遗传学中的不平等现象 通过利用精神病基因组学联盟之间的合作伙伴关系 - 创伤后压力 障碍工作组（PGC-PTSD）和非洲研究人员网络，包括神经精神病学 非洲人口（Neurogap）计划和乌干达基因组资源（UGR）的遗传学。到最后 在2022年，PGC-PTSD将基于多种族元的迄今为止实现PTSD的最大遗传图。 分析> 1,280,000个样本，导致95个风险基因座符合PTSD的基因组意义。超过 发现，最新的PTSD多基因风险评分的工作表明了这些措施在 研究。但是，由于非洲人口的持续不足，这一成功蒙上了阴影 在PTSD遗传研究中，这对PTSD和全球资产的科学进步构成了挑战。 非洲基因组的特征是较短的单倍型块，并且含有近一百万个变体 个人比非洲以外的人口。非洲人口中遗传标记之间的较低相关性 也可用于精细映射引起疾病的等位基因。但是，非洲基因组的差异也会导致 在有限的多基因风险评分的跨种群可传递性中，并且通过扩展的性能较差 非洲的未表征人群。 PTSD的最新进展有很大的风险 遗传学将导致非洲人群的大规模研究和治疗差异扩大。这 鉴于非洲面临的创伤和PTSD的燃烧不成比例，不平等尤其令人不安 在美国和非洲大陆的人口。那是遗传研究中非洲人口的数据 PTSD对于产生遗传危险因素的完整情况至关重要，确定潜在缺失的新颖新颖 治疗信号通过研究所有人群而获得的信号，并解决日益严重的健康不平等。我们建议 通过完成以下特定目的来解决这种不平等：（1）扩展PGC – PTSD样本库 来自非洲大陆和侨民的27,000多个病例和112,000例控制 非洲血统的驱动样本量超过190,000名参与者（约39,000例，151,000例对照）； （2） 整合整个非洲和非洲侨民的数据并进行分析以扩大PTSD风险基因座的发现；和 （3）利用非洲血统人群来改善映射和基因优先次序并减少健康 通过提高这些人群中PTSD的PR准确性来提高不平等。这些目标与 NIMH战略计划目标1，目标1.2，策略1.2.a“发现基因差异和其他基因组学 导致潜水人群的精神疾病的元素。”