ABSTRACT
OBJECTIVES To conduct a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP).
METHODS Adults of European ancestry were included from 16 cohorts in Europe and North America. CBP cases were defined as those reporting back pain present for >3-6 months; non-cases were included as comparisons (“controls”). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p<5×10−8. Suggestive (p<5×10−7) and genome-wide significant (p<5×10−8) variants were carried forward for replication or further investigation in an independent sample.
RESULTS The discovery sample was comprised of 158,025 individuals, including 29,531 CBP cases. A genome-wide significant association was found for the intronic variant rs12310519 in SOX5 (OR 1.08, p=7.2×10−10). This was subsequently replicated in an independent sample of 283,752 subjects, including 50,915 cases (OR 1.06, p=5.3×10−11), and exceeded genome-wide significance in joint meta-analysis (OR=1.07, p=4.5×10−19). We found suggestive associations at three other loci in the discovery sample, two of which exceeded genome-wide significance in joint meta-analysis: an intergenic variant, rs7833174, located between CCDC26 and GSDMC (OR 1.05, p=4.4×10−13), and an intronic variant, rs4384683, in DCC (OR 0.97, p=2.4×10−10).
DISCUSSION In this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP (SOX5). We also identified 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis (CCDC26/GSDMC and DCC).
Footnotes
B.M.P. serves on the DSMB of a clinical trial funded by Zoll LifeCor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson; Y.S.A. and L.K. are founders and co-owners of PolyOmica, a private genomics research organization; these relationships do not pose known conflicts with the content of this work presented. We the authors do not have any other financial interests that could create a potential conflict or the appearance of a potential conflict of interest with regard to this work.
All grant/financial support for this work is reported in the acknowledgements section of the manuscript.
