Genetic Architecture of the Comorbidity of Alcohol Use Disorder and Chronic Pain

项目摘要/摘要 酒精使用障碍(AUD)和慢性疼痛(CP)通常同时发生。数据表明，历史上 在CP的治疗中，16%-25%的患者报告说有大量饮酒和/或AUD，疼痛已经 被认为是澳门氏症患者复发的主要危险因素之一。两者之间有很大重叠 AUD和CP在神经调节失调方面的研究已有报道，表明遗传影响可能 这是AUD和CP并存的基础。独立检测AUD和CP的遗传学研究 记录了每一种的中等遗传力，以及来自全基因组关联研究(GWAS)的初步证据 在遗传水平上支持重叠。尽管如此，我们目前对基因结构的理解 AUD和CP之间潜在的共病是有限的。拟议中的项目是第一个系统地 通过利用使用摘要和个人级别数据的大规模GWA来弥合这一知识鸿沟 两个主要目标和第三个探索性目标：(主要目标1)估计共有遗传方差量 这有助于潜在的结构总结酒精和CP的表型和独特的遗传变异 使用理论驱动的多变量方法对每种表型作出贡献；(主要目标2)估计 AUD-CP共病可通过共同的遗传机制与因果双向解释的程度 AUD与CP关系的工具变量法和(探索性目标)模型 可能影响基因对发育或维持的贡献的背景主持人 AUD-CP共病。这些关键问题将通过采用最先进的统计方法来解决 遗传学方法，如全基因组结构方程模型、成对GWAS、孟德尔方法 随机化和全基因组复杂性状分析，这些都已经被很好地验证用于研究 精神和身体健康状况之间的遗传关系。因为这些方法在以下方面有所不同 目的和/或假设，将采用多方法方法来评估 并进一步提高科学严谨性。因此，这个项目将促进我们对 遗传和环境因素对AUD、CP及其共病的病因的影响。此外， 该项目的结果将提供初步数据，表明更全面研究的可行性 基因-环境交互作用对未来R01应用中AUD-CP共病的影响。

PROJECT SUMMARY/ABSTRACT Alcohol use disorder (AUD) and chronic pain (CP) commonly co-occur. Data have shown that a history of heavy drinking and/or AUD are reported by 16-25% of patients in treatment for CP, and pain has been identified as one of the major risk factors for relapse among individuals with AUD. Substantial overlap between AUD and CP in terms of neurological dysregulation has been reported suggesting that genetic influences may underlie the co-occurrence of AUD and CP. Genetic studies examining AUD and CP independently have documented moderate heritability of each, and initial evidence from genome-wide association studies (GWAS) supports overlap at the genetic level. Nonetheless, our current understanding of the genetic architecture underlying comorbidity between AUD and CP is limited. The proposed project is the first to systematically bridge this knowledge gap by leveraging large-scale GWAS using summary and individual level data to address two primary aims and a third exploratory aim: (Primary Aim 1) estimate the amount of shared genetic variance that contributes to latent constructs summarizing alcohol and CP phenotypes and the unique genetic variance that contributes to each phenotype using a theory-driven, multivariate approach; (Primary Aim 2) estimate the extent to which AUD-CP comorbidity can be explained by shared genetic mechanisms vs. causal, bidirectional relations between AUD and CP using an instrumental variable approach; and (Exploratory Aim) model contextual moderators that might impact the genetic contributions to the development or maintenance of AUD-CP comorbidity. These critical questions will be addressed by employing state-of-the-art statistical genetics methods, such as genome-wide structural equation modeling, pairwise GWAS, Mendelian randomization, and genome-wide complex trait analysis, which have been well-validated for investigating genetic relations among psychiatric and physical health conditions. Because these methods differ in terms of purposes and/or assumptions, a multimethod approach will be adopted to evaluate the robustness of the findings and further enhance scientific rigor. As a result, this project will advance our understanding of the genetic and environmental contributions to the etiologies of AUD, CP, and their comorbidity. Additionally, the results of this project will provide preliminary data indicating the feasibility of more comprehensively studying the effects of gene-environment interplay on AUD-CP comorbidity in future R01 applications.