Genome-wide Meta-analysis of 158,000 Individuals of European Ancestry Identifies Three Loci Associated with Chronic Back Pain

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).

Insight into the genetic architecture of back pain and its risk factors from a study of 509,000 individuals

“…This reflects the current state of BP research, where there is no universally accepted gold standard for defining BP. 22 Recently established consensus guidelines for core BP definitions may facilitate future efforts to harmonize definitions between cohorts. 64…”

“…For CHARGE Consortium cases were defined as those reporting BP present for at least 3 months, while the controls were defined as those who reported no BP or BP with shorter duration. 65 Thus, the definition of BP in these cohorts corresponded to chronic BP.…”

“…Of the three replicated loci, two have been reported previously as associated with other BP phenotypes: the chromosome 12 lead SNP rs12310519 located in the intron of the SOX5 gene was associated with chronic BP in the recent GWAS by the CHARGE and PainOMICS consortia 22 . The region on chromosome 8 (lead SNP rs7814941), located in an intergenic site of GSDMC and CCDC26 was identified in a study of sciatica, 23 and was among the loci associated with chronic BP at p<5×10 -8 in the GWAS by the CHARGE and PainOMICS consortia, 22 but not previously replicated.…”

“…For replication, we used a combination of the UK Biobank participants not included in the discovery set, and from the CHARGE Consortium 22 Table 1).…”

“…We recently performed a genome-wide association study (GWAS) for chronic BP (BP lasting longer than 3 months) from the interim release of the UK Biobank 21 and from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Musculoskeletal Working Group 22 (total N = 158,000 individuals). Despite a large sample size and relatively well-defined phenotype, the study identified and replicated only three loci associated with chronic BP.…”