Genetic Comorbidity of PTSD and Substance Use Disorders in Diverse Populations.

摘要/项目总结 物质使用障碍（SUD，即，酒精，尼古丁，大麻，阿片类药物）和创伤后应激障碍 创伤后应激障碍（PTSD）是普遍的，高度共病，并与高公共卫生负担。此外，频繁 SUD和PTSD的共同发生具有临床意义，包括症状更严重，治疗更差 预后和不良的身体健康状况。因此，我们非常需要了解 他们的病因学基础，以最好地为预防和干预工作提供信息。SUD和PTSD都是 中度遗传，双胞胎研究证明了相关的遗传风险。统计方面的最新进展 遗传学已经产生了非常适合于共模应用的多变量方法， 检验因果关系的相关性（即，Mendalian随机化[MR]），并提高识别 疾病特异性和共有遗传风险（即，基因组结构方程模型[gSEM]）。我们迄今为止的工作 专注于创伤后应激障碍与酒精使用障碍（AUD）的遗传关系，显示出显著的 PTSD和AUD之间的遗传相关性（rG=.35），并发现PTSD对AUD的因果关系的支持。 虽然这些发现为PTSD和其他常见的SUD之间的关系提供了线索，但遗传学上的研究表明， PTSD与其他SUD，特别是大麻和阿片类药物使用障碍之间的关系仍然相对 未开发的这个项目的第一个目标是利用现有的大型GWAS样本， 精神病学基因组学联盟（PGC）SUD和PTSD工作组，以表征遗传关系 用最先进的统计遗传学技术来分析SUD和PTSD之间的关系PTSD中的初始GWAS 和SUD工作组主要集中在广泛的表型，这些表型可用于协调 同伙因此，在工作组内增加数据收集和协调方面的需求尚未得到满足 让更多关于PTSD-SUD关系的微妙科学问题得到解答。比如说， 尚不清楚PTSD-SUD遗传关系的性质是否受创伤特征的影响（即， 发病年龄，创伤类型），作为物质使用与疾病的函数而不同，以及基因组风险如何 在PTSD-SUD共病病例中展开。这个项目的第二个目的是询问这些更微妙的 通过扩大PGC组内的表型来解决科学问题。重要的是，现有的研究是有限的， 非洲人和拉丁裔的代表性不足。该项目的第三个目标是 在PTSD和SUD PGC工作组中增加不同参与者的参与。我们将决定 目标1的研究结果扩展到非洲和拉丁美洲血统的人口，通过整合三个大的和不同的现有 研究SUD，PTSD和创伤的数据，并建立更多的合作，以增加多样性， PGC工作组。这项建议的首要目标是了解SUD之间的遗传关系， 和创伤后应激障碍，同时增加了精神病遗传学研究中不同血统个体的代表性。

ABSTRACT/PROJECT SUMMARY Substance Use Disorders (SUD, i.e., alcohol, nicotine, cannabis, opioid) and Posttraumatic Stress Disorder (PTSD) are prevalent, highly comorbid, and associated with a high public health burden. Further, the frequent co-occurrence of SUD and PTSD has clinical implications, including greater symptom severity, poorer treatment prognosis, and poor physical health, compared to either disorder alone. Thus, there is a great need to understand their etiologic underpinnings to best inform prevention and intervention efforts. SUD and PTSD are both moderately heritable, with correlated genetic risk demonstrated by twin studies. Recent advances in statistical genetics have produced multivariate methods well suited for comorbidity applications that expand upon genetic correlations to examine causality (i.e., Mendalian Randomization [MR]), and to boost power for identification of disorder-specific and shared genetic risk (i.e., genomic structural equation modeling [gSEM]). Our work thus far has focused on the genetic relationships of PTSD with alcohol use disorder (AUD), demonstrating a significant genetic correlation between PTSD and AUD (rG=.35), and finding a support for a causal effect of PTSD on AUD. While these findings provide clues for the relationships between PTSD and other common SUD, the genetic relationships between PTSD with other SUDs, especially cannabis, and opioid use disorders remain relatively unexplored. The first aim of this project is to harness the existing large GWAS samples brought together by the Psychiatric Genomics Consortium (PGC) SUD and PTSD workgroups, to characterize the genetic relationship between SUDs and PTSD using state-of-the-science statistical genetic techniques. Initial GWAS in the PTSD and SUD workgroups have largely focused on broad phenotypes that are amendable for harmonization across cohorts. Thus, there is an unfilled need for increased data acquisition and harmonization within the workgroups to allow for more nuanced scientific questions about the PTSD-SUD relationship to be answered. For example, it is unknown if the nature of the PTSD-SUD genetic relationship is influenced by trauma characteristics (i.e., age of onset, type of trauma), differs as a function of substance use versus disorder, and how genomic risk unfolds in comorbid PTSD-SUD cases. The second aim of this project is to interrogate these more nuanced scientific questions by expanding phenotyping within the PGC groups. Importantly, existing research is limited by the under-representation of individuals of African and Latinx ancestry. The third aim of this project is to increase inclusion of diverse participants within the PTSD and SUD PGC workgroups. We will determine whether Aim 1 findings extend to populations of African and Latinx ancestry by integrating three large and diverse existing studies with data on SUD, PTSD, and trauma, and build additional collaborations to increase diversity in the PGC workgroups. The overarching goal of this proposal is to understand the genetic relationships between SUD and PTSD while increasing representation of individuals of diverse ancestry in psychiatric genetics research.