Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Neurotransmitter Receptor Gene Polymorphisms Are Associated with Widespread Pain: Findings from the First Genome-Wide Association Study of Musculoskeletal Pain.
Holliday3, Kate L., Neogi2, Tuhina, Felson2, David, Wang1, Ke, Thomson4, Wendy, McBeth4, John
Musculoskeletal pain disorders are prevalent with 10% of the general population reporting widespread pain. Heritability estimates for widespread pain are around 50% although the susceptibility loci have yet to be identified. The purpose of this study was to identify susceptibility loci by conducting the first genome-wide association study (GWAS) of widespread pain.
As part of the Framingham SHARe project, subjects from 3 generations were genotyped using Affymetrix 500k and 50k gene-focused SNP chips. Genotypes were called using the BRLMM algorithm. Samples were excluded for low call rate (<95%), excess heterozygosity and mendelian errors. SNPs were excluded for deviation from HWE (p<10-6), low call rate (<97%), MAF<0.01 and mendelian errors (>100). Whole genome imputation was carried out using HapMap CEU data and MACH v1.0.15. Data on musculoskeletal pain was available for a subset of these subjects (n=3850) from 2 generations. The reporting of painful regions on a homunculus was used to classify cases with widespread pain (reporting pain in contra-lateral body quadrants above and below the waist and in the axial skeleton) and controls (reporting no pain). Generalised estimating equation regression analysis was used to perform a case-control GWAS analysis under an additive genetic model on autosomal SNPs with a MAF>0.03, while accounting for relatedness between subjects and using genomic control to adjust for population stratification in R.
Imputation was conducted on 378,163 SNPs meeting quality control criteria providing 2,321,937 SNPs for analysis in 572 cases and 1587 controls. The genomic inflation factor was 1.02. Using a p-value cut off of 1 × 10-5, we identified 52 SNPs in association with widespread pain which comprise 8 individual loci, many of which are strong candidate loci for susceptibility to widespread pain. In particular, an intronic SNP in the neurotransmitter receptor gene GABA B receptor 2 (GABBR2) was associated with an increased risk of having widespread pain (OR=1.37 (1.24, 1.51) p=6.7 × 10-6). A SNP 100 Kb downstream of another neurotransmitter receptor, glutamate receptor 2 (GRIA2), was also associated with an increased risk of having widespread pain (OR=1.54 (1.35, 1.73) p=8.96 × 10-6).
This study, the first GWAS of widespread pain, implicates a number of biologically relevant loci in neurotransmitter genes that are directly linked to pain pathways. Validation of these findings is now required in independent cohorts to ascertain the true impact of these loci on widespread pain susceptibility and is currently underway.
To cite this abstract, please use the following information:
Holliday, Kate L., Neogi, Tuhina, Felson, David, Wang, Ke, Thomson, Wendy, McBeth, John; Neurotransmitter Receptor Gene Polymorphisms Are Associated with Widespread Pain: Findings from the First Genome-Wide Association Study of Musculoskeletal Pain. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :836