Genetic Architecture of the Comorbidity of Alcohol Use Disorder and Chronic Pain - PROJECT SUMMARY/ABSTRACT Alcohol use disorder (AUD) and chronic pain (CP) commonly co-occur. Data have shown that a history of heavy drinking and/or AUD are reported by 16-25% of patients in treatment for CP, and pain has been identified as one of the major risk factors for relapse among individuals with AUD. Substantial overlap between AUD and CP in terms of neurological dysregulation has been reported suggesting that genetic influences may underlie the co-occurrence of AUD and CP. Genetic studies examining AUD and CP independently have documented moderate heritability of each, and initial evidence from genome-wide association studies (GWAS) supports overlap at the genetic level. Nonetheless, our current understanding of the genetic architecture underlying comorbidity between AUD and CP is limited. The proposed project is the first to systematically bridge this knowledge gap by leveraging large-scale GWAS using summary and individual level data to address two primary aims and a third exploratory aim: (Primary Aim 1) estimate the amount of shared genetic variance that contributes to latent constructs summarizing alcohol and CP phenotypes and the unique genetic variance that contributes to each phenotype using a theory-driven, multivariate approach; (Primary Aim 2) estimate the extent to which AUD-CP comorbidity can be explained by shared genetic mechanisms vs. causal, bidirectional relations between AUD and CP using an instrumental variable approach; and (Exploratory Aim) model contextual moderators that might impact the genetic contributions to the development or maintenance of AUD-CP comorbidity. These critical questions will be addressed by employing state-of-the-art statistical genetics methods, such as genome-wide structural equation modeling, pairwise GWAS, Mendelian randomization, and genome-wide complex trait analysis, which have been well-validated for investigating genetic relations among psychiatric and physical health conditions. Because these methods differ in terms of purposes and/or assumptions, a multimethod approach will be adopted to evaluate the robustness of the findings and further enhance scientific rigor. As a result, this project will advance our understanding of the genetic and environmental contributions to the etiologies of AUD, CP, and their comorbidity. Additionally, the results of this project will provide preliminary data indicating the feasibility of more comprehensively studying the effects of gene-environment interplay on AUD-CP comorbidity in future R01 applications.
