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

慢性疼痛状况和内化精神病理学，遗传流行病学调查。

• 批准号: 10595497
• 负责人: Marianna Gasperi
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595497
• 关键词: Address; Algorithms; American; Anxiety Disorders; Attention; Biometry; Chromosome Mapping; Chronic Fatigue Syndrome; Clinical Data; Clinical Research; Data; Development; Diagnosis; Disease; Economics; Electronic Health Record; Etiology; Evaluation; Fibromyalgia; Genes; Genetic; Genetic Determinism; Genetic Models; Genetic Predisposition to Disease; Goals; Grant; Health Care Costs; Health Services Accessibility; Heritability; Impairment; Improve Access; Individual; Intervention; Investigation; Irritable Bowel Syndrome; Knowledge; Link; Linkage Disequilibrium; Literature; Maps; Mediating; Mendelian randomization; Mental Depression; Mental disorders; Mentors; Methodology; Methods; Migraine; Modeling; Molecular Genetics; Mood Disorders; Pain; Pain intensity; Phenotype; Post-Traumatic Stress Disorders; Prognosis; Psychopathology; Public Health; Quality of life; Quantitative Genetics; Reading; Research; Research Ethics; Research Personnel; Resources; Risk; Role; Sample Size; Sampling; Series; Severities; Single Nucleotide Polymorphism; Susceptibility Gene; Temporomandibular Joint Disorders; Tension Headache; Testing; Therapeutic Intervention; Training; Translational Research; Treatment outcome; Twin Multiple Birth; Twin Studies; United States Department of Veterans Affairs; Veterans; Writing; chronic pain; chronic painful condition; comorbidity; cost; design; epidemiology study; genetic epidemiology; genetic variant; genome wide association study; genome-wide; improved; military veteran; novel; observational cohort study; opioid epidemic; opioid use; personalized medicine; precision medicine; prescription opioid; programs; research and development; research study; risk sharing; sex; skills; social; symposium; trait

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.

抽象的。患有偏头痛、纤维肌痛和烦躁等慢性疼痛的退伍军人 肠道综合征经常表现出共病的内化精神疾病，例如情绪和焦虑 失调。慢性疼痛和内化障碍之间的共病加剧了病程 两者都会导致阿片类药物使用增加和生活质量低下，并导致更差的治疗结果。 虽然双胞胎研究表明，双胞胎之间的遗传和环境影响存在大量重叠。 个体慢性疼痛状况和内化障碍，识别特定遗传变异的进展 这种关系的基础是缓慢的。迄今为止，还没有研究评估慢性病之间的关系。 使用分子遗传学方法的疼痛状况和内化障碍，这些方法允许 特定基因的识别，代表了我们对病因学理解的重大知识差距 这些条件。为了解决明显的研究差距，目前的 CDA-2 包括一个观察队列 研究使用百万退伍军人计划 (MVP) 提供的数据来检验两者之间的关系 慢性疼痛和内化障碍。 MVP 代表了独特而强大的资源 通过结合广泛的电子健康记录 (EHR) 和 全基因组遗传数据。使用来自这个大型且具有代表性的样本的数据，具体目标是：1) 从 EHR 中得出慢性疼痛和内化障碍表型； 2）评估之间的遗传重叠 使用全基因组关联研究和联系进行慢性疼痛和内化障碍 不平衡（LD）-分数回归； 3）探索慢性疼痛、内化之间的因果关系 疾病和阿片类药物使用孟德尔随机化方法。该提案的优点包括使用 大规模 EHR 和遗传数据揭示遗传对慢性疼痛合并症的影响 状况和内化障碍，以及多种慢性疼痛状况和内化的评估 立刻出现紊乱。了解慢性疼痛和慢性疼痛之间的共同遗传病因 内化障碍以及潜在的因果机制将为推进治疗提供目标 干预并促进从遗传流行病学到个性化医疗的进展。 拟议的 CDA-2 将为候选人提供必要的培训和研究机会 推进慢性疼痛和内化障碍之间的遗传共病模型并提供支持 她的长期目标是成为退伍军人管理局的一名独立研究员，重点研究遗传流行病学 慢性疼痛和精神疾病的研究，以及精准医学方法的发展 治疗患有这些病症的退伍军人。具体培训目标包括 1) 熟练使用 用于临床和转化研究的 EHR 数据； 2）正规的分子遗传学培训； 3）扩展 了解疼痛机制和阿片类药物使用的实质性问题； 4）研究 道德、资助写作和专业发展。培训计划由一个环环相扣的计划组成 课程作业、强化指导、阅读小组、研讨会系列和会议，特别关注 研究伦理培训。每个拟议培训领域的领先专家的直接指导是 该提案的基本特点：主要导师 Niloofar Afari 博士（疼痛表型），共同导师 Drs. Niloofar Afari（疼痛表型） Richard Hauger（MVP 专业知识）、Murray Stein（EHR 数据和精神病表型）和 Caroline Nievergelt（统计遗传学）和顾问博士。马修·帕尼松（定量遗传学）、詹姆斯·墨菲 （电子病历）、马克·华莱士（疼痛和阿片类药物的使用）和韦斯利·汤普森（生物统计学）。候选人将使用这些 完成研究的具体研究目标的技能和资源。 CDA-2 的调查结果 可能大大增加对慢性疼痛与内化联系机制的理解 疾病，并导致对退伍军人的这些衰弱疾病进行有针对性的精准医学干预。