Integrative genomic and environmental study to understand central sensitization and the etiology of chronic overlapping pain conditions

Background and Innovation: Chronic overlapping pain conditions (COPCs), including migraine, irritable bowel syndrome, chronic back pain, fibromyalgia, chronic fatigue syndrome, and chronic prostatitis/chronic pelvic pain syndrome, impose a profound burden on Veterans. Marked by persistence and high co-occurrence, these conditions significantly impair quality of life, leading to substantial disability and high healthcare costs. Veterans are at higher risk of chronic pain and COPCs due to stressors and exposures associated with military service, including physical trauma, psychological stress, and toxicant exposure. Individuals with both COPCs and internalizing (INT) disorders (post-traumatic stress disorder, depression, anxiety) show worse treatment outcomes, increased impairment, and greater use of opioid medications. Central sensitization (CS) – the amplification of the central nervous system – provides a theoretical framework for understanding symptoms ranging from subtle, early indicators to full-blown COPC. Critical gaps remain in understanding the shared CS liability across multiple COPCs and INT disorders, the temporal progression of these conditions from subclinical symptoms, the shared genetic architecture among CS conditions, and the interplay between genetic and environmental factors like toxicant exposure and COPC onset. This limited understanding hampers our ability to identify COPC risk and personalize treatments, perpetuating the cycle of chronic pain and disability. Using Million Veteran Program (MVP) data, we will address these critical gaps within the Veteran population, whose unique experiences provide rare context for understanding complex interactions between genetic liability and environmental exposures. We aim to evaluate the timing and relationships between subclinical CS symptoms, INT, and COPC onset using longitudinal EHR, conduct time- to-event GWAS to evaluate the genetic contribution to time of COPC onset, and evaluate gene-by-environment interaction with military toxicant exposures on the risk of developing COPCs. Finally, we will explore models integrating genetic, environmental, and clinical data to anticipate COPC onset. Significance and Impact to Veteran Healthcare: Chronic pain is the most critical health challenge confronting Veterans, followed closely by INT disorders. The bidirectional relationship between COPCs and INT worsens health outcomes and complicates treatment for Veterans, leading to disability and substance use problems. Our work is relevant to the millions of Veterans with or at risk of COPC and INT disorders. By clarifying the genetic and environmental underpinnings of CS, COPC, and the INT relationship, we will better understand CS etiology and interplay with environmental hazards. This work will inform efforts to identify high risk for COPCs and associated CS problems, encouraging personalized care. Path to Translation/Implementation: In addition to improving our understanding of CS and COPC etiology, this work will facilitate a shift from reactive to proactive management of COPCs by laying the foundation for early CS and COPC detection. Our work lays the groundwork for a transformative change in clinical practice and pain risk identification. In addition to advancing our understanding of the genetic underpinnings and etiological factors contributing to CS and COPCs—an endeavor that has the potential to inform the development of novel therapeutics and drug studies—we foresee future efforts building on this proposal by integrating predictive models into clinical decision support systems within EHR. This work will facilitate personalized care informed by genetic, environmental, and clinical patient profiles. Training programs and educational resources can be evaluated to empower providers and patients to adopt these innovations, while continuous data collection can refine the models. Pilot studies and expanded clinical trials can validate these approaches, paving the way for mo Project Number: 1I01RD001420-01A1 | Fiscal Year: 2026 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Marianna Gasperi | Institution: VA PUGET SOUND HEALTHCARE SYSTEM, SEATTLE, WA | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 NURP-N (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11299650