A Multi-Omics Investigation of Risk and Resilience for Opioid Use Disorder Among Chronic Pain Patients

About This Grant

Significance to VA: This CDA-2 application requests support for a 5-year mentored research project to identify multi-omics risk and resilience factors for opioid use disorder (OUD) and chronic pain, conditions that disproportionately burden Veterans. Veterans face elevated OUD risk due to higher rates of chronic pain and opioid exposure than the general population, yet key genetic and environmental contributors to risk and resilience are poorly understood. This project will address these gaps by leveraging genomic and bioinformatic methods to improve prevention and treatment strategies. The proposed research aligns with the mission of the Veterans Healthcare Administration by focusing on the intersection of chronic pain and OUD—high-priority issues with substantial disease burden—and advancing precision medicine approaches to improve treatment outcomes for Veterans. It will provide me with training to support my development as an early-career investigator committed to improving the care of Veterans with chronic pain who are risk for OUD. Innovation and Impact: The proposed research is innovative in its focus on resilience to OUD, representing the first multi-omics analysis of this phenomenon in Veterans with chronic pain. The integration of genetic, epigenetic, transcriptomic, and proteomic data using network-based machine learning models will enable a holistic understanding of biological pathways that drive OUD and chronic pain. These novel, transformative methods align with state-of-the-art data science approaches to translate genomic findings into actionable insights. The project establishes a framework for integrating multi-omics findings with clinical data, paving the way for precision medicine approaches tailored to Veterans’ unique needs. These innovations will advance scientific knowledge and clinical care to help alleviate the burdens of OUD and chronic pain among Veterans. Specific Aims: (1) Identify genetic variants associated with OUD risk and resilience in Veterans with chronic pain and examine how clinical factors moderate these associations. (2) Characterize epigenetic changes linked to risk and resilience factors in Veterans. (3) Integrate multi-omics (genetic, epigenetic, and in silico predicted transcriptomic and proteomic) data using network-based machine learning models to identify key biological pathways and gene networks that underlie risk and resilience to OUD and chronic pain. Methodology: The proposed study employs an integrative multi-omics approach to investigate OUD and chronic pain in Veterans, leveraging data from the Million Veteran Program (MVP). Genome-wide association studies will identify genetic variants associated with risk and resilience, epigenome-wide association studies will assess methylation changes, and multi-omics data will be integrated using network-based machine learning models. Key outcomes include the identification of genetic and epigenetic contributors to OUD resilience and the elucidation of underlying biological pathways. The population of interest is Veterans with chronic pain. Comparison groups include Veterans with and without OUD to delineate factors that distinguish resilience from risk. Data sources are MVP genomic, epigenomic, and phenotypic datasets, and predicted transcriptomic and proteomic data using publicly available reference sources. Path to Translation/Implementation: A core element of this research is its clear translational pathway to improving Veterans’ healthcare. Immediate steps will leverage identified biological pathways and gene networks to develop biomarkers for OUD risk and resilience in chronic pain patients. These biomarkers could inform clinical decision-making, such as identifying high-risk Veterans and tailoring pain management strategies to their individual genetic and epigenetic profiles. Longer-term goals include using foundational insights to inform therapy development, including precision medicine approaches that target pathways identified in the study. Through collaborations with the VA’s clinical and research infrastructure, we aim to ultimately translate findings into interventions that reduce OUD risk and alleviate chronic pain among Veterans.