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: 10755801
• 负责人: Marianna Gasperi
• 金额: --
• 依托单位: VA PUGET SOUND 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/10755801
• 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。患有慢性疼痛状况的退伍军人，例如偏头痛，纤维肌痛和烦躁 肠综合征经常表现出合并的内在化精神病状况，例如情绪和焦虑 疾病。慢性疼痛状况与内在疾病之间的合并症加剧了课程 两者都有助于增加鸦片使用和生活质量较低，并导致较差的治疗结果。 虽然双胞胎研究表明遗传和环境影响重叠 单个慢性疼痛状况和内在疾病，识别特定遗传变异的进展 这种关系的基础很慢。迄今为止，尚无研究评估慢性的关系 疼痛状况和使用分子遗传学方法的内在疾病，那些允许的疾病 识别特定基因，代表我们对病因的理解的重要知识差距 这些条件。为了解决明显的研究差距，目前的CDA-2包括一个观测队列 使用百万退伍军人计划（MVP）可用数据的研究来检查 慢性疼痛状况和内在疾病。 MVP代表了一个独特而强大的资源 通过广泛的电子健康记录（EHR）和 全基因组遗传数据。使用来自该大型和代表性样本的数据，具体目的是：1） 从EHR中得出慢性疼痛和内在障碍表型； 2）评估遗传重叠 使用全基因组关联研究和联系的慢性疼痛状况和内在疾病 不平衡（LD） - 分数回归； 3）探索慢性疼痛之间的因果关系，内在化 疾病和阿片类药物与孟德尔随机化方法的使用。提案的优势包括使用 大规模的EHR和遗传数据揭示了慢性疼痛合并症的遗传贡献 疾病和内在疾病，评估多种慢性疼痛状况并内在化 一次疾病。了解慢性疼痛条件和 内部化疾病以及潜在的因果机制将为预防治疗性提供目标 干预并促进从遗传流行病学到个性化医学的发展。 拟议的CDA-2将为候选人提供必要的培训和研究机会 提高慢性疼痛状况和内在疾病和支持的遗传合并症模型 她的长期目标是成为VA中的独立研究人员，重点是遗传流行病学 慢性疼痛和精神疾病，以及精确医学的发展方法 在这些条件下对退伍军人的处理。具体的培训目标包括1）熟练使用 EHR临床和转化研究数据； 2）分子遗传学的正式培训； 3）扩展 了解疼痛机制和使用阿片类药物的基本问题的知识； 4）研究 道德，赠款写作和专业发展。培训计划包括一个互锁计划 课程工作，密集的指导，阅读小组，研讨会系列和会议，特别关注 研究伦理培训。在每个提议的培训领域的领先专家的直接指导是一个 该提案的基本特征：主要导师，Niloofar Afari博士（疼痛表型），联合董事Drs。 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Drs。 Matthew Panizzon（定量遗传学），詹姆斯·墨菲（James Murphy） （EHR），Mark Wallace（疼痛和阿片类药物的使用）和Wesley Thompson（生物统计学）。候选人将使用这些 完成研究的特定研究目的的技能和资源。此CDA-2的发现具有 有可能大大了解将慢性疼痛和内在化的机制理解 疾病并导致对退伍军人中这些使人衰弱状况的有针对性的精确医学干预措施。