7. PSYCHIATRIC GENETIC LIABILITY DIFFERENTIATES LONGITUDINAL PAIN PROFILES IN THE MILLION VETERAN PROGRAM

Background Pain is a highly heterogeneous experience that varies in severity, persistence, progression, and fluctuation over time. Existing studies of pain trajectories have often relied on relatively small samples, short follow-up periods, or infrequent assessments, limiting the ability to characterize the full complexity of longitudinal pain experiences. As a result, the factors that contribute to distinct patterns of pain over time remain poorly understood. Leveraging large-scale longitudinal electronic health record data may provide an opportunity to better characterize pain heterogeneity and identify genetic liabilities associated with pain profiles. Methods Participants included 624,996 Veterans from the Million Veteran Program with outpatient Numeric Rating Scale pain assessments available. Across participants, more than 51 million pain scores were available, with individuals followed longitudinally for an average of 16 years. To characterize longitudinal pain experiences, we conducted latent profile analysis using four indicators: (1) mean pain severity across follow-up, (2) slope of change in pain over time, (3) within-person variability in pain measured using the root mean square of successive differences, and (4) maximum yearly mean pain score. To evaluate clinical correlates of the identified profiles, we examined rates of pain-related diagnoses across profile groups. We then investigated genetic associations with pain profile membership using multinomial regression models and polygenic scores (PGS) derived from the PGS Catalog. Analyses were conducted separately across five genetically-inferred ancestry groups. Results A four-profile solution provided the best fit to the data and identified longitudinal pain patterns characterized as: stable no pain, stable mild pain, mild-to-moderate increasing pain, and fluctuating mild-to-moderate pain. The profiles differed meaningfully in rates of pain-related diagnoses, with individuals in the increasing pain profile having the highest burden of pain-related clinical conditions. Several psychiatric and behavioral PGS were associated with increased likelihood of membership in higher-severity pain profiles relative to the stable no pain profile. In particular, higher PGS for depression, insomnia, attention-deficit hyperactivity disorder (ADHD), and tobacco use disorder were consistently associated with greater odds of membership in the stable mild pain, increasing pain, and fluctuating pain profiles than the stable no pain profile. Associations were strongest for the mild-to-moderate increasing pain profile and generally followed a graded pattern. Discussion This study represents the largest investigation of longitudinal pain profiles to date. The associations between psychiatric and behavioral polygenic scores and higher-severity pain profiles supports the substantial shared etiology between pain and psychiatric phenotypes. Depression, insomnia, ADHD, and tobacco use disorder liabilities were most strongly associated with increasing and fluctuating pain trajectories, suggesting that psychiatric genetic risk may contribute not only to overall pain severity, but also to instability and worsening of pain over time.