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

酒精使用障碍和慢性疼痛合并症的遗传结构

• 批准号: 10741891
• 负责人: IAN ROBERT GIZER
• 金额: $ 42.42万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-02 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10741891
• 关键词: Address; Adopted; Alcohol abuse; Alcohol dependence; Alcohols; Back Pain; Biological; Classification; Complex; Data; Development; Dimensions; Disease; Elderly; Environment; Environmental Impact; Environmental Risk Factor; Equation; Etiology; Future; Genes; Genetic; Genetic Heterogeneity; Genetic Models; Genetic Structures; Genetic study; Genomics; Genotype; Goals; Heavy Drinking; Heritability; High Prevalence; Human; Hyperalgesia; Individual; Intervention; Investigation; Joints; Knowledge; Lead; Literature; Longevity; Maintenance; Measures; Mendelian randomization; Methods; Modeling; Nature; Neck Pain; Neurologic; Pain; Pathology; Pathway interactions; Patients; Persons; Phenotype; Play; Precision therapeutics; Process; Public Health; Recording of previous events; Relapse; Reporting; Research Personnel; Rewards; Risk; Risk Factors; Role; Sampling; Scientist; Stress; System; Testing; Work; alcohol abuse therapy; alcohol comorbidity; alcohol use disorder; chronic pain; chronic pain management; chronic painful condition; comorbidity; contextual factors; coping; design; genetic architecture; genetic information; genetic variant; genome wide association study; genome-wide; individualized prevention; insight; instrument; novel; physical conditioning; problem drinker; prospective; societal costs; theories; trait

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.

项目摘要/摘要 酒精使用障碍（AUD）和慢性疼痛（CP）通常共同发生。数据表明， 大量饮酒和/或AUD由16-25％的患者接受CP的治疗，疼痛一直是 被确定为AUD个人复发的主要风险因素之一。两者之间的重叠 据报道，在神经功能失调方面，AUD和CP表明遗传影响可能 AUD和CP的共同发生的基础。独立研究AUD和CP的基因研究具有 每种都有中度遗传力，以及全基因组关联研究（GWAS）的初步证据 支持在遗传水平上重叠。但是，我们目前对遗传结构的理解 AUD和CP之间的基本合并症是有限的。拟议的项目是系统的 通过利用摘要和个人级别数据来解决这个知识差距 两个主要目的和第三个探索目的：（主要目的1）估计共享遗传差异的数量 这有助于潜在构造总结酒精和CP表型以及独特的遗传差异 使用理论驱动的多元方法有助于每种表型。 （主要目的2）估计 可以通过共享的遗传机制与因果关系，双向的共同遗传机制来解释哪种AUD-CP合并症的程度 使用仪器变量方法在AUD和CP之间的关系；和（探索目的）模型 上下文主持人可能会影响遗传贡献的发展或维护 AUD-CP合并症。这些关键问题将通过使用最先进的统计来解决 遗传学方法，例如全基因组结构方程建模，成对GWAS，Mendelian 随机化和全基因组的复杂性状分析，这些特征已得到充分研究 精神病和身体健康状况之间的遗传关系。因为这些方法在 目的和/或假设，将采用一种多方法的方法来评估 发现并进一步增强了科学严谨性。结果，该项目将促进我们对 遗传和环境对AUD，CP及其合并症的病因的贡献。另外， 该项目的结果将提供初步数据，表明更全面地研究的可行性 基因环境相互作用对未来R01应用中AUD-CP合并症的影响。