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

项目摘要/摘要 此应用程序的广泛目标是推进创伤后应激障碍基因发现并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-创伤后应激之间的伙伴关系进行研究 障碍工作组(PGC-PTSD)和包括神经精神科在内的非洲调查人员网络 非洲种群遗传学(NeuroGAP)计划和乌干达基因组资源(UGR)。到了最后 到2022年，PGC-PTSD将实现迄今为止基于多种族元的最大PTSD基因图谱 分析了1280,000个样本，导致95个风险基因座满足整个基因组对创伤后应激障碍的意义。超越 发现，最近关于创伤后应激障碍多基因风险评分的工作表明，这些测量方法在 研究。然而，由于非洲人口的代表性持续偏低，这种成功黯然失色。 在创伤后应激障碍基因研究方面，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。 非洲的基因组以较短的单倍型区块为特征，并且每个基因组包含近一百万个变种 非洲以外的人口比个人更多。非洲人群中遗传标记之间的相关性较低 对精细定位致病等位基因也很有用。然而，非洲基因组的差异也导致了 多基因风险得分的跨人群可转移性有限，进而在 没有特征的人群，例如来自非洲的人群。创伤后应激障碍的最新进展有很大风险 遗传学将导致非洲人口的巨大研究和治疗差距扩大。这 鉴于非洲人面临的创伤和创伤后应激障碍负担过重，不平等尤其令人担忧。 美国和非洲大陆的人口。因此，在基因研究中来自非洲人口的数据 对于生成完整的遗传风险因素、识别潜在缺失的小说 通过研究所有人群获得治疗信号，并解决日益严重的健康不平等问题。我们建议 通过实现以下具体目标解决这一不平等问题：(1)扩大PGC-PTSD样本库 有超过27,000个病例和来自非洲大陆和海外侨民的11.2万个控制措施，以实现强大的，良好的- 超过190,000名非洲血统参与者(约39,000例，151,000名对照)的研究样本规模；(2) 整合整个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基因的发现；以及 (3)利用非洲血统人口改善精细图谱和基因优先顺序，并减少健康 在这些人群中，通过提高创伤后应激障碍的精确度来改善不平等。这些目标与以下目标高度一致 NIMH战略计划目标1、目标1.2、战略1.2A“发现基因变异和其他基因组学” 在不同的人群中导致精神疾病的因素。

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.”