Genetic overlap between chronic pain, substance use disorders, and nucleus accumbens volume

Substance use disorders are highly prevalent in chronic pain populations. Substances may have unique genetic relationships with pain or act through a shared genetic liability. One proposed explanation for the co-occurrence of pain and smoking is that smoking may directly chronify pain by promoting maladaptive plasticity of the reward pathway, which involves the nucleus accumbens. Using genome-wide association study (GWAS) statistics, we tested whether a chronic pain factor is genetically correlated with a substance use liability factor, whether there is any additional shared genetic risk specific to different substances beyond the general substance use factor, and whether the nucleus accumbens volume genetically mediates the smoking-pain association. We used European ancestry association statistics from four GWASs of substance use – cigarettes per day, and alcohol, opioid, and cannabis use disorder (sample sizes (n) = 37,003 to 337,334); GWASs of seven chronic pain conditions – headache, neck/shoulder, back, stomach, hip, knee, and wide-spread (n = 251,857 to 522,962); and a GWAS of nucleus accumbens volume (n = 13,171). We used linkage disequilibrium score regression to calculate genetic correlations and used genomic structural equation modeling to fit models based on these genetic correlations. Within European ancestry populations, there are moderate genetic correlations between substance use and chronic pain conditions (rg = 0.08-0.60). The strongest genetic correlation is between chronic widespread pain and alcohol use disorder. There is also a strong genetic correlation between the general chronic pain and substance use factors (rg = 0.64, p < 0.001). Smoking shares genetic risk with the chronic pain factor over and above the substance use factor (rg = 0.28, p < 0.001). The nucleus accumbens volume does not significantly genetically relate to either smoking or the chronic pain factor. The findings suggest that substance use disorder liability and chronic pain share genetic risk. Additionally, smoking has a unique genetic risk with chronic pain above the substance use factor. These results have implications for pain management, as individuals seeking pain treatment may be at higher genetic risk for substance use liability. We plan to conduct Mendelian randomization to test causality of smoking on pain chronification.