Understanding the comorbidities among psychiatric disorders, chronic low-back pain, and spinal degenerative disease using observational and genetically informed analyses.

Psychiatric disorders and symptoms are associated with differences in pain perception and sensitivity. These differences can have important implications in treating spinal degenerative disease (SDD) and chronic low-back pain (CLBP). Leveraging data from the UK Biobank (UKB) and the All of Us Research Program (AoU), we investigated the effects linking psychiatric disorders (alcohol use disorder, anxiety, attention deficit hyperactivity disorder, bipolar disorder, cannabis use disorder, depression, opioid use disorder, posttraumatic stress disorder, and schizophrenia) to SDD and CLBP. We applied multi-nominal regression models, polygenic risk scoring (PRS), and one-sample Mendelian randomization (MR) to triangulate the effects underlying the associations observed. We also performed gene ontology and drug-repurposing analyses to dissect the biology shared among mental illnesses, SDD, and CLBP. Comparing individuals affected only by SDD (UKB N=37,745, AoU N=3,477), those affected only by CLBP (UKB N=15,496, AoU N=23,325), and those affected by both conditions (UKB N=11,463, AoU N= 13,451) to controls (UKB N=337,362, AoU N= 117,162), observational and genetically informed analyses highlighted that the strongest effects across the three case groups were observed for alcohol use disorder, anxiety, depression, and posttraumatic stress disorder. Additionally, schizophrenia and its PRS appeared to have an inverse relationship with CLBP, SDD, and their comorbidity. One-sample MR highlighted a potential direct effect of internalizing disorders on the outcomes investigated that was particularly strong on SDD. Our drug-repurposing analyses identified histone deacetylase inhibitors as targeting molecular pathways shared among psychiatric disorders, SDD, and CLBP. In conclusion, these findings support that the comorbidity among psychiatric disorders, SDD, and CLBP is due to the contribution of direct effects and shared biology linking these health outcomes. These pleiotropic mechanisms together with sociocultural factors play a key role in shaping the SDD-CLBP comorbidity patterns observed across the psychopathology spectrum.