Noncoding rare variants in PANX3 are associated with chronic back pain

Back pain is the leading cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this condition. The impact of genetics is known for the chronic back pain: its heritability is estimated to be at least 40%. Large genome-wide association studies have shown that common variation may account for up to 35% of chronic back pain heritability; rare variants may explain a portion of the heritability not explained by common variants. In this study, we performed the first gene-based association analysis of chronic back pain using UK Biobank imputed data including rare variants with moderate imputation quality. We discovered two genes, SOX5 and PANX3 , influencing chronic back pain. The SOX5 gene is well known back pain gene. The PANX3 gene has not previously been described as having a role in chronic back pain. We showed that the association of PANX3 with chronic back pain is driven by rare non-coding intronic polymorphisms. This result has been replicated on the independent sample from UK Biobank and validated using similar phenotype, dorsalgia, from FinnGen Biobank. We also found that the PANX3 gene is associated with intervertebral disc disorders. We can speculate that a possible mechanism of action of the PANX3 on the back pain is due to its effect on the intervertebral discs.