Chronic pain gene expression changes in the brain and relationships with clinical traits

Background Chronic pain is a common, poorly-understood condition. Genetic studies including genome wide association studies (GWAS) identify many relevant variants, which have yet to be translated into full understanding of chronic pain. Transcriptome wide association study using transcriptomic imputation (TI) methods such as S-PrediXcan can help bridge this genotype-phenotype gap. Methods We carried out TI using S-PrediXcan to identify genetically regulated gene expression (GREX) in thirteen brain tissues and whole blood associated with Multisite Chronic Pain (MCP). We then imputed GREX for over 31,000 Mount Sinai Bio Me ™ participants and performed phenome-wide association study (PheWAS) to investigate clinical relationships in chronic pain associated gene expression changes. Results We identified 95 experiment-wide significant gene-tissue associations (p<7.97×10−7), including 35 unique genes, and an additional 134 gene-tissue associations reaching within-tissue significance, including 53 additional unique genes. Of 89 unique genes total, 59 were novel for MCP and 18 are established drug targets. Chronic pain GREX for 10 unique genes was significantly associated with cardiac dysrhythmia, metabolic syndrome, disc disorders/ dorsopathies, joint/ligament sprain, anemias, and neurological disorder phecodes. PheWAS analyses adjusting for mean painscore showed associations were not driven by mean painscore. Conclusions We carried out the largest TWAS of any chronic pain trait to date. Results highlight potential causal genes in chronic pain development, and tissue and direction of effect. Several gene results were also drug targets. PheWAS results showed significant association for phecodes including cardiac dysrhythmia and metabolic syndrome, indicating potential shared mechanisms. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement KJAJ is supported by NIMH (R01MH118278; R01MH124839). JSJ and LMH are supported by the Klarman Family Foundation. LMH is supported by NIMH (R01MH118278; R01MH124839) and the US National Institute of Environmental Health Sciences (R01ES033630). ### 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: Founded in September 2007, BioMe(TM) is a biobank that links genetic and electronic medical record (EMR) data for over 30,000 individuals recruited primarily in ambulatory care settings in the Mount Sinai Health System (MSHS) in New York City. The current study was approved by the Icahn School of Medicine at Mount Sinai Institutional Review Board. All study participants provided written informed consent. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. GWAS summary statistics for multisite chronic pain are available online at http://dx.doi.org/10.5525/gla.researchdata.822