Chronic Back Pain Linked to Three Genetic Variants


An international team of scientists has identified three novel genetic variants associated with chronic back pain. Their study (“Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain”), published in PLOS Genetics, links the risk for back pain with variants in genes controlling skeletal development, among other pathways. These findings may help to elucidate the basic biology underlying this common symptom, and point toward avenues for the eventual development of new therapies, according to the researchers.

“Back pain is the number one cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). Adults of European ancestry were included from 15 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and from the UK Biobank interim data release. 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 the remaining UK Biobank participants not included in the discovery sample. The discovery sample comprised 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 283,752 UK Biobank participants not included in the discovery sample, 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),” write the investigators.

“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). In this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP (SOX5). We also identified two other loci that reached genome-wide significance in a two-stage joint meta-analysis (CCDC26/GSDMC and DCC).”

The GWAS involved 158,000 adults, including over 29,000 individuals with chronic back pain, looking for gene variants that were associated with the presence of back pain. The strongest association was with a variant in the SOX5 gene, which is a transcription factor involved in virtually all phases of embryonic development. Inactivation of SOX5 has previously been linked to defects in cartilage and skeleton formation in mice, supporting the hypothesis that the variant discovered in this study may contribute to chronic back pain through its influence on some aspect of skeletal development. 

The association of the SOX5 variant with chronic back pain was replicated in another group of over 280,000 individuals, including over 50,000 individuals with chronic back pain. A second gene, previously associated with intervertebral disc herniation, was also linked to back pain, as was a third gene that plays a role in spinal cord development, possibly implicating pain sensation or mood in the risk for back pain.

“The results of our genome-wide association study point to multiple pathways that may influence risk for chronic back pain,” says Pradeep Suri, M.D., of the Department of Veterans Affairs in Seattle. “Chronic back pain is linked to changes in mood, and the role of the central nervous system in the transition from acute to chronic back pain is well recognized. However, the top two genetic variants we identified suggest causes implicating the peripheral structures, such as the spine. We expect that further large-scale genetic studies will reveal the importance of both peripheral and central contributors to the complex experience of chronic back pain.”

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