Chronic pain conditions and internalizing psychopathology, a genetic epidemiology investigation.

抽象的。患有慢性疼痛的退伍军人，如偏头痛、纤维肌痛和易怒 肠道综合征常常表现为情绪和焦虑等内在性精神疾病的并存。 精神错乱。慢性疼痛状况和内化障碍之间的共病加剧了病程。 这两者都会增加鸦片类药物的使用，降低生活质量，并导致更糟糕的治疗结果。 虽然双胞胎研究表明，在遗传和环境影响方面存在很大重叠 个体慢性疼痛状况和内化性疾病，识别特定基因变异的进展 这种关系的基础一直很缓慢。到目前为止，还没有研究评估慢性疾病之间的关系 使用分子遗传学方法的疼痛状况和内在性障碍，这些方法允许 特定基因的识别，代表了我们在理解疾病病因方面的显著知识差距。 这些条件。为了解决这一明显的研究差距，目前的CDA-2包括了一个观察队列 使用百万退伍军人计划(MVP)提供的数据进行研究，以检查 慢性疼痛状况和内化性障碍。MVP代表着一种独特而强大的资源 通过结合广泛的电子健康记录(EHR)和 全基因组的遗传数据。使用来自这个具有代表性的大样本的数据，具体目的是：1) 从EHR中获得慢性疼痛和内在性障碍的表型；2)评估 应用全基因组关联研究和连锁研究慢性疼痛状况和内化性疾病 不平衡(LD)-分数回归；3)探索慢性疼痛、内在化之间的因果关系 障碍，以及使用孟德尔随机化方法的阿片类药物。该提案的优点包括使用 大规模EHR和遗传学数据揭示基因对慢性疼痛共病的影响 条件和内化障碍，以及对多种慢性疼痛条件和内化的评估 一下子就失控了。了解慢性疼痛和慢性疼痛之间的共同遗传病因 内在化障碍以及潜在的致病机制将为推进治疗提供靶点 干预和促进从遗传流行病学到个性化医学的进展。 拟议的CDA-2将为候选人提供必要的培训和研究机会，以 提出慢性疼痛状况与内在性疾病和支持的遗传共病模型 她的长期目标是成为退伍军人事务部的一名独立研究员，专注于遗传流行病学 慢性疼痛和精神障碍的治疗，以及治疗慢性疼痛和精神障碍的精确医学方法的发展 对患有这些疾病的退伍军人的治疗。具体的培训目标包括：1)熟练使用 用于临床和转译研究的电子病历数据；2)分子遗传学方面的正规培训；3)扩展 关于疼痛机制和阿片类药物使用的实质性问题的知识；以及4)研究 道德、助学金写作和职业发展。培训计划包括一项连锁计划， 课程作业、强化辅导、阅读小组、系列研讨会和会议，并特别注意 研究伦理方面的培训。每个拟议培训领域的主要专家的直接指导是 这项建议的基本特征：主要导师，Niloofar Afari博士(疼痛表型)，共同导师Dr. 理查德·豪格(MVP专长)、默里·斯坦(EHR数据和精神病学表型)和卡罗琳 Nieverglt(统计遗传学)，以及顾问Matthew Panizzon博士(数量遗传学)，James Murphy (EHR)，Mark Wallace(疼痛和阿片类药物使用)，和Wesley Thompson(生物统计学)。应聘者将使用这些 技能和资源，以实现研究的具体研究目标。这项CDA-2的研究结果具有 有可能大幅增加对慢性疼痛和内化联系机制的理解 并导致对退伍军人的这些衰弱状况进行有针对性的精准医学干预。

ABSTRACT. Veterans with chronic pain conditions such as migraine headache, fibromyalgia, and irritable bowel syndrome frequently manifest comorbid internalizing psychiatric conditions such as mood and anxiety disorders. The comorbidity between chronic pain conditions and internalizing disorders exacerbates the course of both, contributes to increased opiate use and low quality of life, and leads to worse treatment outcomes. While twin studies have indicated substantial overlap in genetic and environmental influences between individual chronic pain conditions and internalizing disorders, progress in identifying specific genetic variants underlying this relationship has been slow. To date, no studies have evaluated the relationship among chronic pain conditions and internalizing disorders using molecular genetic methodology, those that allow for the identification of specific genes, representing a significant knowledge gap in our understanding of the etiology of these conditions. To address the glaring research gap, the present CDA-2 includes an observational cohort study using data available from the Million Veteran Program (MVP) to examine the relationship between chronic pain conditions and internalizing disorders. The MVP represents a unique and powerful resource for evaluating these relationships through the combination of extensive electronic health record (EHR) and genome-wide genetic data. Using data from this large and representative sample, the specific aims are to: 1) derive chronic pain and internalizing disorder phenotypes from EHR; 2) evaluate the genetic overlap between chronic pain conditions and internalizing disorders using genome-wide association study and linkage disequilibrium (LD)-score regression; and 3) explore the causal relationships among chronic pain, internalizing disorders, and opioid use with Mendelian randomization methods. Strengths of the proposal include the use of large-scale EHR and genetic data to reveal the genetic contributions to the comorbidity among chronic pain conditions and internalizing disorders, and the evaluation of multiple chronic pain conditions and internalizing disorders at once. Understanding the shared genetic etiologies between chronic pain conditions and internalizing disorders as well as potential causal mechanisms will provide targets for advancing therapeutic intervention and facilitate the progression from genetic epidemiology to personalized medicine. The proposed CDA-2 will provide the candidate the training and research opportunities necessary to advance a model of genetic comorbidity among chronic pain conditions and internalizing disorders and support her long-term goal of becoming an independent researcher within the VA with a focus on genetic epidemiology of chronic pain and psychiatric disorders, and the development of precision medicine approaches to the treatment of Veterans with these conditions. Specific training goals include 1) gaining proficiency in the use of EHR data for clinical and translational research; 2) formal training in molecular genetics; 3) expanding knowledge of substantive issues underlying pain mechanisms and opioid medication use; and 4) research ethics, grant writing, and professional development. The training plan consists of an interlocking program of coursework, intensive mentoring, reading groups, seminar series, and conferences, with special attention to training in research ethics. Direct mentoring from leading experts in each of the proposed training domains is a fundamental feature of this proposal: primary mentor, Dr. Niloofar Afari (pain phenotyping), co-mentors Drs. Richard Hauger (MVP expertise), Murray Stein (EHR data and psychiatric phenotyping), and Caroline Nievergelt (statistical genetics), and consultants Drs. Matthew Panizzon (quantitative genetics), James Murphy (EHR), Mark Wallace (pain and opioid use), and Wesley Thompson (biostatistics). The candidate will use these skills and resources to accomplish the specific research aims of the study. Findings from this CDA-2 have the potential to substantially increase understanding of the mechanisms that link chronic pain and internalizing disorders and lead to targeted precision medicine interventions of these debilitating conditions in Veterans.