Sex-stratified genome-wide association study of multisite chronic pain in UK Biobank

Johnston, K. J.A. et al. (2021) Sex-stratified genome-wide association study of multisite chronic pain in UK Biobank. PLoS Genetics, 17(4), e1009428. (doi: 10.1371/journal.pgen.1009428) (PMID:33830993) (PMCID:PMC8031124)

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Chronic pain is highly prevalent worldwide and imparts a significant socioeconomic and public health burden. Factors influencing susceptibility to, and mechanisms of, chronic pain development, are not fully understood, but sex is thought to play a significant role, and chronic pain is more prevalent in women than in men. To investigate sex differences in chronic pain, we carried out a sex-stratified genome-wide association study of Multisite Chronic Pain (MCP), a derived chronic pain phenotype, in UK Biobank on 178,556 men and 209,093 women, as well as investigating sex-specific genetic correlations with a range of psychiatric, autoimmune and anthropometric phenotypes and the relationship between sex-specific polygenic risk scores for MCP and chronic widespread pain. We also assessed whether MCP-associated genes showed expression pattern enrichment across tissues. A total of 123 SNPs at five independent loci were significantly associated with MCP in men. In women, a total of 286 genome-wide significant SNPs at ten independent loci were discovered. Meta-analysis of sex-stratified GWAS outputs revealed a further 87 independent associated SNPs. Gene-level analyses revealed sex-specific MCP associations, with 31 genes significantly associated in females, 37 genes associated in males, and a single gene, DCC, associated in both sexes. We found evidence for sex-specific pleiotropy and risk for MCP was found to be associated with chronic widespread pain in a sex-differential manner. Male and female MCP were highly genetically correlated, but at an rg of significantly less than 1 (0.92). All 37 male MCP-associated genes and all but one of 31 female MCP-associated genes were found to be expressed in the dorsal root ganglion, and there was a degree of enrichment for expression in sex-specific tissues. Overall, the findings indicate that sex differences in chronic pain exist at the SNP, gene and transcript abundance level, and highlight possible sex-specific pleiotropy for MCP. Results support the proposition of a strong central nervous-system component to chronic pain in both sexes, additionally highlighting a potential role for the DRG and nociception.

Item Type:Articles
Additional Information:RJS is supported by a UKRI Innovation- HDR-UK Fellowship (MR/S003061/1). JW is supported by the JMAS Sim Fellowship for depression research from the Royal College of Physicians of Edinburgh (173558). KJAJ is supported by an MRC Doctoral Training Programme Studentship at the Universities of Glasgow and Edinburgh (MR/N013166/1). DJS acknowledges the support of a Lister Prize Fellowship (173096) and the MRC Mental Health Data Pathfinder Award (MC_PC_17217). M.J.A. and A.M.M. are supported by Pathfinder Award MC_PC_17209 and by Wellcome Trust Grant 104036/Z/14/Z. TJP and PRR are supported by a National Institute of Neurological Disorders and Stroke (Bethesda) grant (R01NS102161).
Glasgow Author(s) Enlighten ID:Smith, Professor Daniel and Nicholl, Dr Barbara and Bailey, Dr Mark and Ward, Dr Joey and Johnston, Ms Keira and Strawbridge, Dr Rona
Authors: Johnston, K. J.A., Ward, J., Ray, P. R., Adams, M. J., McIntosh, A. M., Smith, B. H., Strawbridge, R. J., Price, T. J., Smith, D. J., Nicholl, B. I., and Bailey, M. E.S.
College/School:College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Mental Health and Wellbeing
College of Medical Veterinary and Life Sciences > School of Life Sciences
College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Journal Name:PLoS Genetics
Publisher:Public Library of Science
ISSN (Online):1553-7404
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in PLoS Genetics 17(4):e1009428
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
302131Understanding the excess risk of cardiometabolic disease in individuals with serious mental illnessJill PellMedical Research Council (MRC)MR/S003061/1HW - Public Health
302957Mental Health Data PathfinderDaniel SmithMedical Research Council (MRC)MC_PC_17217HW - Mental Health and Wellbeing