Genome-wide association study suggests a critical contribution of the adaptive immune system to chronic post-surgical pain

Chronic post-surgical pain affects a large proportion of people undergoing surgery, delaying recovery time and worsening quality of life. Although many environmental variables have been established as risk factors, less is known about genetic risk. To uncover genetic risk factors we performed genome-wide association studies in post-surgical cohorts of five surgery types— hysterectomy, mastectomy, abdominal, hernia, and knee— totaling 1350 individuals. Genetic associations between post-surgical chronic pain levels on a numeric rating scale (NRS) and additive genetic effects at common SNPs were evaluated. We observed genome-wide significant hits in almost all cohorts that displayed significance at the SNP, gene, and pathway levels. The cohorts were then combined via a GWAS meta-analysis framework for further analyses. Using partitioned heritability, we found that loci at genes specifically expressed in the immune system carried enriched heritability, especially genes related to B and T cells. The relevance of B cells in particular was then demonstrated in mouse postoperative pain assays. Taken altogether, our results suggest a role for the adaptive immune system in chronic post-surgical pain. ### Competing Interest Statement EAJJ is a consultant for Boston Scientific Inc, and LD was/is a consultant for Duke University, ONO PHARMA USA Inc, Releviate Inc, and Orthogen AG. ### Funding Statement This work was funded by the Canadian Excellence Research Chairs (CERC09), a Pfizer Canada Professorship in Pain Research, and CIHR (SCA-145102) for Health Research's Strategy for Patient-Oriented Research (SPOR) in Chronic Pain to LD. Work also funded by NIH grant P30DA033934 and funds from the Virginia Commonwealth University School of Medicine to MID, and by NIH grant NIDCR08PC10039 to JEC. Work also funded by the Canadian Institutes of Health Research (PJT-362757) to ILK. ### 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: Ethics Comittee of the Maastricht University Medical Center+ approved this work (HYS cohort) Institutional Review Board of the Fondazione Policlinico San Matteo approved this work (ABKNEE cohort) Institutional Review Board of McGill University Faculty of Medecine approved this work (PMPS cohort) Institutional Review Board of the University of Pittsburg approved this work (TKR cohort) Institutional Review Board of the Lundbeck Foundation approved this work (HRN cohort) Institutional Review Board of the University of Iowa Human Subjects Office approved this work (TANK cohort) Institutional Animal Care and Use Committee of Virginia Commonwealth University approved this work (mouse laparotomy) McGill University's Animal Care and Use Committee approved this work (mouse plantar incision) 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