Genetic overlap of chronic pain, musculoskeletal‐specific pain, substance use disorders and substance use consumption: Common addiction and substance‐specific effects

Abstract Background and aims Chronic pain and substance use disorders frequently co‐occur and may share general addiction‐related and substance‐specific genetic pathways. Additionally, substance consumption and problematic use may differ in their genetic associations with pain subtypes. We applied genomic structural equation modeling to assess shared genetic and neurological enrichment between general and musculoskeletal‐specific chronic pain to general addiction liability, substance use disorder‐specific risk and substance use. Design Cross‐trait genomic structural equation modeling using genome‐wide association study (GWAS) summary statistics from large‐scale global consortia. Setting Data were aggregated from international research collaborations and biobanks in the United States and Europe. Participants Participants were individuals ( n = 63 982 to 2 428 851) with European‐like ancestry from population‐based and clinical cohorts. Measurements We analyzed a General Chronic Pain factor from 24 chronic pain GWASs and a Musculoskeletal‐specific Pain factor from 11 overlapping conditions. We constructed an Addiction factor from GWASs of alcohol, tobacco, cannabis and opioid use disorders, and partitioned out substance‐specific genetic risk. We used alcohol and smoking consumption GWASs to distinguish use from problematic use. We applied molecular neurological annotations to assess brain cell type enrichment in shared genetic effects. Findings The Addiction factor was genetically correlated with General Chronic Pain [genetic correlation ( r g ) _ = 0.448, false discovery rate (FDR)‐corrected P < 0.001, 95% confidence interval (95% CI) = 0.40, 0.49], but not with Musculoskeletal‐specific Pain ( r g = 0.001, FDR‐corrected P = 0.998, 95% CI = −0.07 to 0.07). Controlling for Addiction, General Pain had substance‐specific associations: negative correlations with Problematic Alcohol Use ( r g = −0.155, FDR‐corrected P = 0.049, 95% CI = −0.28 to −0.02) and Alcohol Frequency ( r g = −0.334, FDR‐corrected P < 0.001, 95% CI = −0.46 to −0.21), and a positive correlation with Cigarette Frequency ( r g = 0.274, FDR‐corrected P < 0.001, 95% CI = 0.21, 0.34). Musculoskeletal‐specific Pain positively associated with Tobacco Use Disorder ( r g = 0.186, FDR‐corrected P = 0.020, 95% CI = 0.05, 0.32) and Alcohol Frequency ( r g = 0.161, FDR‐corrected P = 0.049, 95% CI = 0.02, 0.30). General Pain related to Cannabis Use Disorder and Opioid Use Disorder entirely through the Addiction factor. Shared genetic components were enriched in excitatory and inhibitory neurons, glia and endothelial cells. Conclusions General chronic pain appears to share substantial genetic overlap and neuronal enrichment with addiction risk and shows distinct associations with problematic alcohol use, alcohol consumption and cigarette use, reflecting both a broad transdiagnostic mechanism as well as substance‐specific paths. In contrast, musculoskeletal‐specific pain appears to be more narrowly linked to tobacco use disorder and alcohol use frequency, but not to general addiction liability.