Using genomics and extensive phenotyping to dissect the relationships between substance use disorders and chronic pain

利用基因组学和广泛的表型分析来剖析物质使用障碍和慢性疼痛之间的关系

基本信息

批准号：
10797779
负责人：
Emma Covey Johnson
金额：
$ 15.55万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10797779
关键词：
Affect Alcohol consumption Alcohols All of Us Research Program Automobile Driving Binding Biological Brain Cannabis Chromosome Mapping Chronic Data Data Analyses Development Diagnosis Discrimination Disease Early Intervention Electronic Health Record Ensure Equation Equity Etiology European ancestry Family Gender Genes Genetic Genetic Risk Genetic Variation Genetic study Genomics Heritability Immunologics Individual Lead Life Link Maps Measures Mediating Mediator Mental Depression Modeling Morbidity - disease rate Musculoskeletal Musculoskeletal Pain Nature Neurologic Neurons Neuropathy Nociception Opioid Outcome Pain Pain Research Pain management Pathway Analysis Pathway interactions Phenotype Population Postoperative Pain Prevention Psychosocial Factor Public Health Recovery Reporting Rewards Risk Risk Factors Role Sample Size Sampling Self Medication Social Environment Source Substance Use Disorder Surveys System Testing Tobacco Tobacco Use Disorder United States Variant Visceral Visceral pain Woman Work addiction alcohol use disorder ancestry analysis biobank biomarker identification biopsychosocial causal variant chronic pain chronic pain management clinical pain cohort comorbidity cost ethnic minority experience gene network genetic risk factor genetic variant genome analysis genome wide association study genomic data genomic locus improved low socioeconomic status marijuana use disorder novel opioid use disorder perceived discrimination phenotypic data pleiotropism psychosocial racial minority rare variant response risk variant rural area social health determinants socioeconomics socioenvironmental factor soft tissue substance use whole genome

项目摘要

Project Abstract Chronic pain is one of the most pressing public health burdens in the United States, affecting up to 20% of the population. Substance use disorders (SUDs) often co-occur with chronic pain. The relationship between chronic pain and opioid use disorder is often attributed to over-use in connection with post-operative pain, but the underlying mechanisms for chronic pain’s comorbidity with other SUDs (alcohol, tobacco, cannabis) are unknown. Depression often co-occurs with both chronic pain and SUDs and could be a mediator of the relationship between pain and SUDs. Socioenvironmental factors, including experiencing discrimination, may also play a role. Given the role of the brain’s reward system in both pain and SUDs, it is also plausible that some of the same genetic risk variants contribute to both chronic pain and SUDs. Both chronic pain and SUDs are moderately heritable and genome-wide association studies have identified loci contributing to their liability. However, these studies have focused on common variants in predominantly European ancestry individuals. This proposal, in response to RFA-PM-23-002, would leverage the multi-ancestral phenotypic and genomic data in All of Us to characterize the relationships between four of the most common SUDs (alcohol, tobacco, cannabis, and opioid use disorders) and chronic pain in a diverse sample. Our first aim will be to curate electronic health records to define a broad measure of chronic pain, as well as more detailed subtypes (e.g., neuropathic vs. nociceptive pain, musculoskeletal vs. visceral pain), and examine how these are related to SUDs. We will test whether a common risk factor, depression, partially mediates the relationship between chronic pain and SUDs. Further, we will estimate the extent to which social determinants of health (e.g., gender, socioeconomic background, experiencing discrimination) are associated with both chronic pain and SUDs. Our second aim will involve whole-genome analyses of chronic pain in multiple ancestries, identifying the genes and pathways that contribute to both chronic pain and SUDs, and employing genetically-informed causal inference models to identify reciprocal relationships. We will use the whole genome sequence data in All of Us to identify genomic factors – common genetic variants, as well as rare variants – that contribute to risk for chronic pain. Next, we will use genomic structural equation modeling and gene network analyses to identify genes and biological pathways that are shared (or distinct) between chronic pain and SUDs. Finally, we will apply multiple causal inference approaches to assess whether there is evidence for causal relationships between chronic pain and SUDs. This proposal will clarify the socioenvironmental and genetic mechanisms associated with chronic pain and SUDs through detailed phenotypic and large-scale genomic analyses on a diverse sample. The findings from these analyses will advance our understanding of why SUDs and chronic pain co-occur, leading to improved treatment and prevention efforts through the identification of shared biological pathways and modifiable psychosocial factors.

项目摘要慢性疼痛是美国最紧迫的公共卫生负担之一，影响着多达 20% 的人物质使用障碍（SUD）通常与慢性疼痛之间的关系。慢性疼痛和阿片类药物使用障碍通常归因于与术后疼痛相关的过度使用，但是慢性疼痛与其他 SUD（酒精、烟草、大麻）共存的根本机制是抑郁症通常与慢性疼痛和 SUD 同时发生，并且可能是慢性疼痛的中介因素。疼痛与 SUD 之间的关系，包括遭受歧视。考虑到大脑奖励系统在疼痛和 SUD 中的作用，这也是合理的。一些相同的遗传风险变异会导致慢性疼痛和 SUD。具有中等遗传性，全基因组关联研究已经确定了导致其责任的基因座。然而，这些研究主要集中在主要是欧洲血统的个体中的常见变异。该提案响应 RFA-PM-23-002，将利用多祖先表型和基因组我们所有人中的数据来描述四种最常见的 SUD（酒精、烟草、大麻和阿片类药物使用障碍）和慢性疼痛的多样化样本。电子健康记录来定义慢性疼痛的广泛衡量标准以及更详细的亚型（例如，神经性疼痛与伤害性疼痛、肌肉骨骼疼痛与内脏疼痛），并检查这些疼痛与我们将测试常见的风险因素抑郁症是否部分介导了两者之间的关系。此外，我们将估计健康的社会决定因素（例如，性别、社会经济背景、经历歧视）与慢性疼痛和我们的第二个目标是对多个祖先的慢性疼痛进行全基因组分析，识别出慢性疼痛。导致慢性疼痛和 SUD 的基因和途径，并采用遗传信息我们将使用全基因组序列数据来识别相互关系的因果推理模型。我们所有人都要识别导致风险的基因组因素——常见的遗传变异以及罕见的变异接下来，我们将使用基因组结构方程模型和基因网络分析来识别。最后，我们将探讨慢性疼痛和 SUD 之间共有（或不同）的基因和生物途径。应用多种因果推理方法来评估是否有因果关系的证据该提案将阐明慢性疼痛和 SUD 之间的社会环境和遗传机制。通过详细的表型和大规模基因组分析，发现与慢性疼痛和 SUD 相关的这些分析的结果将加深我们对 SUD 和慢性病的理解。疼痛同时发生，通过识别共同的疼痛来改善治疗和预防工作生物途径和可改变的社会心理因素。