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Chronic multisite musculoskeletal pain (CMP) is common and highly morbid. However, vulnerability factors for CMP are poorly understood. Previous studies have independently shown that both small hippocampal brain volume and genetic risk alleles in a key stress system gene,  FKBP5 , increase vulnerability for chronic pain. However, little is known regarding the relationship between these factors and CMP. Here we tested the hypothesis that both small hippocampal brain volume and  FKBP5  genetic risk, assessed using the tagging risk variant,  FKBP5 rs3800373, increase vulnerability for CMP. We used participant data from 36,822 individuals with available genetic, neuroimaging, and chronic pain data in the UK Biobank study. Although no main effects were observed, the interaction between  FKBP5  genetic risk and right hippocampal volume was associated with CMP severity (β = −0.020, p raw  = 0.002, p adj  = 0.01). In secondary analyses, severity of childhood trauma further moderated the relationship between  FKBP5  genetic risk, right hippocampal brain volume, and CMP (β = −0.081, p = 0.016). This study provides novel evidence that both  FKBP5  genetic risk and childhood trauma moderate the relationship between right hippocampal brain volume and CMP. The data increases our understanding of vulnerability factors for CMP and builds a foundation for further work assessing causal relationships that might drive CMP development.

Hippocampal volume, FKBP5 genetic risk alleles, and childhood trauma interact to increase vulnerability to chronic multisite musculoskeletal pain