Journal Article

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

Johnston, Keira J. A., Ray, Pradipta R., McIntosh, Andrew M., Bailey, Mark E. S., Smith, Blair H., Nicholl, Barbara I., Ward, Joey, Adams, Mark J., Strawbridge, Rona J., Smith, Daniel J., Price, Theodore J.

2021

Overview

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 r g 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Alleles / Analysis / Annotations / Biobanks / Biological Specimen Banks / Biology and Life Sciences / Bipolar disorder / Chromosomes / Chronic pain / Chronic Pain - epidemiology / Chronic Pain - genetics / Chronic Pain - pathology / Circadian rhythms / Female / Females / Gender differences / Gene expression / Genetic aspects / Genetic Predisposition to Disease / Genetic Testing / Genome-wide association studies / Genome-Wide Association Study / Genomes / Genomics / Genotype & phenotype / Humans / Identification and classification / Inflammatory bowel diseases / Intestine / Male / Males / Medicine and Health Sciences / Meta-analysis / Methods / Middle Aged / Mood / Movement disorders / Neurodegenerative diseases / Pain / Parkinson's disease / Phenotypes / Physical Sciences / Polymorphism, Single Nucleotide - genetics / Research and Analysis Methods / Rheumatoid arthritis / Self destructive behavior / Self-injury / Sex Characteristics / Sexes / Single nucleotide polymorphisms / Single-nucleotide polymorphism / Statistical analysis / Suicide / Suicides & suicide attempts / United Kingdom - epidemiology / Womens health