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

不同人群中 PTSD 和药物使用障碍的遗传共病。

• 批准号: 10658078
• 负责人: ANANDA B AMSTADTER
• 金额: $ 69.48万
• 依托单位: SUNY DOWNSTATE MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658078
• 关键词: African; Age of Onset; Alcohol consumption; Alcohols; Cannabis; Categories; Characteristics; Clinical; Collaborations; Communities; Data; Disease; Equation; Etiology; Feeling suicidal; Genes; Genetic; Genetic Research; Genetic Risk; Genetic Techniques; Genomics; Goals; Heritability; Individual; Intervention; Latinx; Measures; Mendelian randomization; Methods; Modeling; Molecular; Nature; Nicotine; Observational Study; Opioid; Participant; Pathway interactions; Phenotype; Population; Population Heterogeneity; Post-Traumatic Stress Disorders; Prevention; Prognosis; Public Health; Randomized; Research; Risk; Sampling Studies; Science; Severities; Sex Differences; Statistical Methods; Structure; Substance Use Disorder; Symptoms; Testing; Trauma; Twin Studies; Work; alcohol use disorder; cohort; comorbidity; data acquisition; data harmonization; genetic architecture; genome wide association study; genome-wide; genomic variation; marijuana use disorder; novel; opioid use disorder; phenotypic data; physical conditioning; psychiatric genomics; psychogenetics; public health relevance; risk sharing; substance use; success; trait

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.

摘要/项目摘要 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）普遍存在，共病率很高，并且与较高的公共卫生负担相关。此外，频繁 SUD 和 PTSD 同时发生具有临床意义，包括症状更严重、治疗效果更差 与单独的任何一种疾病相比，预后和身体健康状况不佳。因此，非常有必要了解 它们的病因学基础可以为预防和干预工作提供最好的信息。 SUD 和 PTSD 都是 具有中等遗传性，双胞胎研究证明具有相关的遗传风险。统计领域的最新进展 遗传学已经产生了非常适合于合并症应用的多变量方法，这些方法扩展了遗传 相关性来检查因果关系（即孟德尔随机化 [MR]），并增强识别能力 特定疾病和共同的遗传风险（即基因组结构方程模型 [gSEM]）。到目前为止我们的工作 专注于 PTSD 与酒精使用障碍 (AUD) 的遗传关系，证明了显着的 PTSD 和 AUD 之间的遗传相关性 (rG=.35)，并为 PTSD 对 AUD 的因果影响找到支持。 虽然这些发现为 PTSD 和其他常见 SUD 之间的关系提供了线索，但遗传因素 PTSD 与其他 SUD（尤其是大麻）和阿片类药物使用障碍之间的关系仍然相对 未经探索。该项目的首要目标是利用由 GWAS 收集的现有大型 GWAS 样本。 精神病基因组学联盟 (PGC) SUD 和 PTSD 工作组，描述遗传关系 使用最先进的统计遗传技术来区分 SUD 和 PTSD。 PTSD 中的初始 GWAS 和 SUD 工作组主要关注广泛的表型，这些表型可以修改以实现跨领域的协调 队列。因此，工作组内增加数据采集和协调的需求尚未得到满足 以便回答有关 PTSD-SUD 关系的更细致的科学问题。例如， 目前尚不清楚 PTSD-SUD 遗传关系的性质是否受到创伤特征的影响（即， 发病年龄、创伤类型），随着物质使用与疾病的函数以及基因组风险的不同而有所不同 出现在共病 PTSD-SUD 病例中。该项目的第二个目标是询问这些更细致的问题 通过扩大 PGC 群体内的表型分析来解决科学问题。重要的是，现有研究有限 非洲和拉丁裔血统的人代表性不足。该项目的第三个目标是 增加 PTSD 和 SUD PGC 工作组中不同参与者的包容性。我们将确定是否 目标 1 通过整合现有的三个大型且多样化的群体，研究结果扩展到非洲和拉丁血统人群 研究 SUD、PTSD 和创伤的数据，并建立更多合作以增加多样性 PGC 工作组。该提案的总体目标是了解 SUD 之间的遗传关系 和创伤后应激障碍（PTSD），同时增加精神科遗传学研究中不同血统个体的代表性。