Genetic Architecture of Chronic Back Pain: A Multi-Ancestry Genome-Wide Association Study in The Million Veteran Program

This multi-ancestry meta-analysis of genome-wide association studies investigated the genetic factors underlying chronic back pain (CBP) in a large and diverse sample from the Million Veteran Program. A total of 553,601 Veterans of African (19.2%), European (72.6%) and Hispanic (8.2%) ancestry were included. The results revealed 87 loci (67 novel) with 90 independent variants. 85 variants had available summary statistics in (Bjornsdottir, 2023). 57 replicated at the nominal significance threshold (p<0.05) and 26 variants replicated at the Bonferroni-corrected threshold (p<0.05/85=0.000556). The most significant novel variant was rs12533005 (chr7:114416000, p=1.61x10-20, OR=0.96 (95% CI: 0.95-0.97), EA=C, EAF=0.39) in an intron of the FOXP2 gene. In silico functional characterization revealed enrichment in brain and pituitary tissues. Notably, the variants rs11596214 (SORCS3) and rs36030569 (MDGA2), expression quantitative trait loci (eQTLs) in nerve and brain tissues emerged as potential influencers of CBP. Moreover, rs2298526, an eQTL for NCAM1 in skeletal muscle was identified, suggesting its relevance to the musculoskeletal system's role in pain. The observed scale heritability for CBP varied across ancestries: 0.0592 (SE 0.0021) for European, 0.0447 (SE 0.0058) for African and 0.0402 (SE 0.0071) for Hispanic ancestries. Despite a lower genetic predisposition African and Hispanic populations demonstrated a higher CBP prevalence suggesting impact of socio-environmental factors. Strong positive genetic correlations were observed with several psychiatric and mental health-related phenotypes. Our findings more than double the number of previously reported genetic predictors across all spinal pain phenotypes highlighting the importance of large-scale diverse multi-ancestry genetic studies in understanding complex conditions like CBP. Funding: IK2 CX002107, I01RX004291, K23-AT010487.