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

项目总结/摘要 这项申请的广泛目标是推进创伤后应激障碍遗传发现和解决创伤后应激障碍遗传学中的不平等问题 利用精神病学基因组学联盟-创伤后压力之间的伙伴关系进行研究 精神疾病工作组（PGC-PTSD）和非洲调查人员网络，包括神经精神病学研究所， 非洲人群遗传学（NeuroGAP）计划和乌干达基因组资源（UGR）。年底 到2022年，PGC-PTSD将实现迄今为止最大的PTSD基因图谱， 分析> 1，280，000个样本，导致95个风险位点满足PTSD的全基因组意义。超出 发现，最近的工作多基因风险评分在创伤后应激障碍显示了潜在的效用，这些措施， research.然而，非洲人口的代表性一直不足， 这对创伤后应激障碍的科学进步和全球公平都构成了挑战。 非洲基因组的特点是较短的单倍型块，并包含近100万个变异，每 非洲以外的人口。非洲人群中遗传标记之间的相关性较低 也可用于精细定位致病等位基因。然而，非洲基因组的差异也导致了 多基因风险评分的交叉人群可转移性有限，并且，通过扩展， 来自非洲等地的无特征种群。创伤后应激障碍的最新进展 遗传学将导致非洲人口的大规模研究和治疗差距扩大。这 考虑到非洲人所面临的创伤和创伤后应激障碍的负担不成比例地高， 美国和非洲大陆的人口。因此，遗传学研究中来自非洲人群的数据 的创伤后应激障碍是至关重要的，以产生一个完整的图片遗传风险因素，确定潜在的缺失的新的 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。我们提出 通过实现以下具体目标来解决这种不平等：（1）扩大PGC-PTSD样本库 来自非洲大陆和海外的27，000多例病例和112，000例控制，以实现一个强大的，良好的- 超过190，000名非洲血统参与者（约39，000例病例，151，000例对照）的有效样本量;（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风险位点的发现; (3)利用非洲血统人口来改善精细绘图和基因优先排序， 通过提高这些人群中PTSD的PRS准确性来改善不平等。这些目标与 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。”

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.”