Genome-wide Meta-analysis of 158,000 Individuals of European Ancestry Identifies Three Loci Associated with Chronic Back Pain
By
Pradeep Suri,
Melody R Palmer,
Yakov A. Tsepilov,
Maxim B Freydin,
Cindy G Boer,
Michelle S Yau,
Daniel S Evans,
Andrea Gelemanovic,
Traci M Bartz,
Maria Nethander,
Liubov Arbeeva,
Lennart Karssen,
Tuhina Neogi,
Archie Campbell,
Dan Mellstrom,
Claes Ohlsson,
Lynn M Marshall,
Eric Orwoll,
Andre Uitterlinden,
Jerome I. Rotter,
Gordan Lauc,
Bruce M Psaty,
Magnus K Karlsson,
Nancy E Lane,
Gail Jarvik,
Ozren Polasek,
Marc Hochberg,
Joanne M Jordan,
Joyce B. J. Van Meurs,
Rebecca Jackson,
Carrie M Nielson,
Braxton D Mitchell,
Blair H Smith,
Caroline Hayward,
Nicholas L. Smith,
Yurii Aulchenko,
Frances MK Williams
Posted 08 Jan 2018
bioRxiv DOI: 10.1101/244483
(published DOI: 10.1371/journal.pgen.1007601)
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<5x10-8. Suggestive (p<5x10-7) and genome-wide significant (p<5x10-8) 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=7.2x10-10). This was subsequently replicated in an independent sample of 283,752 subjects, including 50,915 cases (OR 1.06, p=5.3x10-11), and exceeded genome-wide significance in joint meta-analysis (OR=1.07, p=4.5x10-19). 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=4.4x10-13), and an intronic variant, rs4384683, in DCC (OR 0.97, p=2.4x10-10). 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).
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