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

项目摘要 慢性疼痛是美国最紧迫的公共卫生负担之一，影响多达20%的 人口。物质使用障碍(SODS)通常与慢性疼痛并存。两国之间的关系 慢性疼痛和阿片类药物使用障碍通常归因于与术后疼痛有关的过度使用，但 慢性疼痛与其他肥皂水(酒精、烟草、大麻)共病的潜在机制是 未知。抑郁症经常与慢性疼痛和肥皂水并存，并可能是 疼痛和肥皂水之间的关系。社会环境因素，包括经历歧视，可能 也起到了一定作用。考虑到大脑的奖赏系统在疼痛和肥皂水中的作用，也有可能 一些相同的基因风险变异会同时导致慢性疼痛和肥皂水。慢性疼痛和肥皂水 是适度可遗传的，全基因组关联研究已经确定了导致它们易感性的基因。 然而，这些研究主要集中在以欧洲血统为主的个体中的常见变异。 这一建议，作为对RFA-PM-23-002的回应，将利用多祖先的表型和基因组 我们所有人的数据来描述四种最常见的肥皂之间的关系(酒精，烟草， 大麻、阿片类药物使用障碍)和慢性疼痛在不同的样本中。我们的首要目标是 电子健康记录，以定义慢性疼痛的广泛测量以及更详细的子类型(例如， 神经病理性疼痛与伤害性疼痛、肌肉骨骼疼痛与内脏疼痛)，并研究这些与 肥皂水。我们将测试一个共同的风险因素，抑郁，是否部分调节了 慢性疼痛和肥皂水。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、遭受歧视)与慢性疼痛和 肥皂水。我们的第二个目标将涉及对多个祖先的慢性疼痛进行全基因组分析，确定 导致慢性疼痛和肥皂症的基因和途径，并使用遗传信息 确定相互关系的因果推理模型。我们将使用全基因组序列数据 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 治疗慢性疼痛。接下来，我们将使用基因组结构方程建模和基因网络分析来识别 慢性疼痛和肥皂症共有(或不同)的基因和生物途径。最后，我们会 应用多种因果推理方法来评估是否存在因果关系的证据 在慢性疼痛和肥皂水之间。这项提议将阐明社会环境和遗传机制。 通过对一种慢性疼痛和肥皂水的详细的表型和大规模基因组分析 多样化的样本。这些分析的发现将促进我们对肥皂水和慢性肥胖症的理解 疼痛共同发生，通过识别共享的 生物途径和可改变的心理社会因素。

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.