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


Autoři: Keira J. A. Johnston aff001;  Joey Ward aff001;  Pradipta R. Ray aff004;  Mark J. Adams aff002;  Andrew M. McIntosh aff002;  Blair H. Smith aff005;  Rona J. Strawbridge aff001;  Theodore J. Price aff004;  Daniel J. Smith aff001;  Barbara I. Nicholl aff001;  Mark E. S. Bailey aff003
Působiště autorů: Institute of Health and Wellbeing, University of Glasgow, Glasgow, Scotland, United Kingdom aff001;  Division of Psychiatry, University of Edinburgh, Edinburgh, Scotland, United Kingdom aff002;  School of Life Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom aff003;  School of Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, Texas, United States of America aff004;  Division of Population Health Sciences, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, United Kingdom aff005;  Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden aff006
Vyšlo v časopise: Sex-stratified genome-wide association study of multisite chronic pain in UK Biobank. PLoS Genet 17(4): e1009428. doi:10.1371/journal.pgen.1009428
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1009428

Souhrn

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.

Klíčová slova:

Gene expression – Genetic loci – Genetics – Genome-wide association studies – Human genetics – Metaanalysis – Pain – Single nucleotide polymorphisms


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