Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain

Abstract

Back pain is the #1 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). 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 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis (CCDC26/GSDMC and DCC).

Genome-Wide Association Study of Opioid Cessation

“…The analgesic effect of opioids might explain the positive association between chronic pain and opioid cessation. In addition, the Netrin-1 receptor gene, DCC, was related to chronic opioid exposure and chronic back pain in both mice and human studies [73,74].…”

Genetic, lifestyle and environmental risk factors for chronic pain revealed through GWAS

“…Genome-wide SNP Heritability was calculated using LDSC. We transformed the h 2 estimate from observed to liability scale using prevalence estimates of our sample (73%) and a population prevalence of 50 % [12,23,30,51,53,75,85,86,91,92] using the commands --samp-prev 0.73 and -- pop-prev 0.5. The liability scale heritability corrects for ascertainment bias regarding the prevalence of the condition.…”

“…Evidence for the role of genetic factors in CP comes from twin and family studies [38] where its heritability is estimated to be as high as 60% [11,37]. More recently, large-scale genome-wide association studies (GWAS) have identified multiple genetic variants associated with chronic back pain [25,75] and multisite chronic pain [36] as further evidence of a genetic contribution to CP. However, their causal relationship has yet to be adequately examined.…”

Can Implementation of Genetics and Pharmacogenomics Improve Treatment of Chronic Low Back Pain?

“…Another significant CBP-associated gene variant is the lead SNP rs4384683, an intronic variant in the gene DCC (deleted in colorectal carcinoma) [21]. Netrin-1 is an axonal guidance molecule, and as such, participates in the development of cortical and spinal commissural neurons.…”

“…Neurovascular ingrowth into the IVD may be mediated by netrin-1 and DCC, which is a mechanism that has long been implicated in chronic discogenic back pain [25,26]. Given the phenotypic correlation between CBP and depression [27], the correlation between CBP and DCC (depressive symptoms associated with cross phenotype of rs4384683) could also be explained by pleiotropy [21]. In animal models of mechanical allodynia, interactions of Netrin1/DCC have been found to impact pain processing in the spinal cord [23].…”