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

ABSTRACT 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. Competing Interest Statement RP reports receiving personal fees from Karger Publishers and a grant from Alkermes outside the submitted work. The other authors declare no conflict of interest. Funding Statement The authors acknowledge support from the National Institutes of Health (RF1MH132337 and R33DA047527) and One Mind. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: UKB data can be requested at https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access. All of Us Research Program data are available at https://allofus.nih.gov/get-involved/opportunities-researchers. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data generated in the present study are reported in the manuscript and its supplemental material.