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.

PROJECT NARRATIVE. Over 100 million Americans and approximately 50% of U.S. military Veterans suffer from chronic pain. Research indicates a strong, bidirectional link between chronic pain conditions and internalizing psychiatric disorders and individuals with both chronic pain conditions and internalizing disorders show worse treatment prognosis, increased impairment, and greater use of opioid medication. While the association between chronic pain and internalizing disorders is well documented, the underlying mechanisms that drive the association remain elusive. This CDA-2 project will use electronic health record and genetic data from the Million Veterans Program to identify the genetic factors common to the development of these conditions and sets the stage for progression from genetic epidemiology to precision medicine. Improved understanding of the mechanism underlying this relationship can reduce negative consequences such as opiate use, healthcare costs and societal burden, and improve access to care for Veterans.