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

Abstract

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, FKBP5rs3800373, 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, praw = 0.002, padj = 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.

Genetic risk shared across 24 chronic pain conditions: identification and characterization with genomic structural equation modeling

“…52 Of the 241 genes mapped to independent significant SNPs from the general factor GWAS, FKBP5 is the only one previously targeted in a candidate gene study (as opposed to GWAS) for posttraumatic musculoskeletal pain. 9,59,119 .…”

Adverse childhood experience is associated with an increased risk of reporting chronic pain in adulthood: a stystematic review and meta-analysis

“…Adult patients exposed to ACEs may not be achieving optimal health outcomes due to the physiological and psychological effects of toxic stress (Tidmarsh et al, 2022 ; Werthman et al, 2022 ). While the relative contributions of these mechanisms are not yet well understood, emerging evidence links ACEs to changes in genetic expressions that affect structural and functional changes in the brain and clinical phenomena in adulthood (Lobo et al, 2022 ). ACEs may be associated with heightened pain sensitivity later in life (Pierce et al, 2023 ).…”

Hippocampal volume changes across developmental periods in female migraineurs

“…Glucocorticoids, among other mediators, are involved in this plasticity that can include increases in dendritic arborization, synapses and neurogenesis as well as decreases in volume of specific brain regions and circuit ( [6] , [12] , [2] ). Previous research has repeatedly demonstrated that both chronic stress and chronic pain can have profound effects on hippocampal structure and function ( [48] , [53] ). Alterations in hippocampal structure have been demonstrated in multiple chronic pain conditions ( [42] , [63] , [24] , [49] , [71] , [19] ), notably including migraine ( [4] , [47] , [50] ).…”

“…In a large cohort of adults, evidence was also found associating hippocampal volume with the number of body pain sites ( Lobo et al, 2022 ) and increased pain sensitivity ( Mutso et al, 2012 ). The hippocampus has also been strongly implicated as playing a role in the fear network, which is strongly and intricately related to pain processing ( [75] , [48] , [43] ). In peripubertal animal paradigms, chronic stress produces alterations in hippocampal volume, and stress (HPA) axis functioning ( Isgor et al, 2004 ).…”