The inflammatory and genetic mechanisms underlying the cumulative effect of co-occurring pain conditions on depression

Abstract

Chronic pain conditions frequently coexist and share common genetic vulnerabilities. Despite evidence showing associations between pain and depression, the additive effect of co-occurring pain conditions on depression risk and the underlying mechanisms remain unclear. Leveraging data from 431,038 UK Biobank participants with 14-year follow-up, we found a significantly increased risk of depression incidence in individuals reporting pain, irrespective of body site or duration (acute or chronic), compared with pain-free individuals. The depression risk increased with the number of co-occurring pain sites. Mendelian randomization supported potential causal inference. We constructed a composite pain score by combining individual effects of acute or chronic pain conditions across eight body sites in a weighted manner. We found that depression risks increased monotonically in parallel with composite pain scores. Moreover, some inflammatory markers, including C-reactive protein, partially mediated the association between composite pain scores and depression risk. Considering the high prevalence of comorbid depression and pain, pain screening may help identify high-risk individuals for depression.

Fig. 1.. Overview of study workflow.

Leveraging 431,038 participants from UK Biobank with a 14.22-year follow-up, this study investigated the prospective association between pain conditions and depression risks, which were further replicated on matched data using a propensity score matching procedure. We also used MR to make causal inferences about the effect of pain conditions on depression. We then examined the independent and joint associations of pain conditions across eight body sites and varying duration with depression incidence. Last, using 14 inflammatory markers extracted from hematological assays, we explored inflammatory markers as a potential mechanism driving the association between pain and depression.

Fig. 2.. Prospective associations of acute or chronic pain across eight body sites and incidence of depression.

(A) Compared with pain-free individuals, those with pain showed a significantly increased risk of developing depression, irrespective of body site, duration, and adjustment for multiple covariates. (B) Interaction analyses supported a significantly modifying effect of age on the association of pain in the neck, back, hip, and knee with the depression risk, with participants aged younger than 65 years showing a higher depression risk than their older counterparts. The error bar and horizontal lines indicate the corresponding 95% CI. The size of the bars and the internal center represent mean HRs.

Fig. 3.. Prospective and causal associations of MCP with incident depression.

(A) Compared with pain-free individuals, those with acute pain, SCP, and MCP had a higher depression risk after adjustment for covariates and multiple comparisons, and depression risks increased along with the number of co-occurring pain sites. (B) Exposure-response curve between the number of co-occurring pain sites and depression risks was nonlinear, with plateauing trends at lower exposure but steeper slopes at higher exposure. (C) Significant interaction between pain status and age and between pain status and education attainment was observed. The dashed vertical line indicates the significance threshold after correcting for multiple testing [−log(0.05/13) =2.41]. Specifically, the associations tended to be higher in people younger than 65 years for SCP and MCP. Individuals with acute pain having a college degree showed a higher risk of depression than those without a college degree. (D) MR estimates provided evidence for a significantly detrimental effect of MCP on depression. The scatterplot shows SNP effects on MCP and depression.

Fig. 4.. The independent association between each pain condition and the risk of depression after mutually adjusting for the other pain conditions.

Dots indicate mean HRs, and the horizontal lines indicate the corresponding 95% CI.

Fig. 5.. Association of inflammatory markers with composite pain scores and depression incidence.

(A) Strong evidence supported a nonlinear association between composite pain scores and depression risks, with linear trends at lower exposure and steeper slopes at higher exposure. Compared with pain-free individuals, those in the lowest, middle, and highest tertile of composite pain scores demonstrated a 1.22-fold, 1.43-fold, and 2.25-fold elevated risk of depression incidence, respectively. (B) Of all 14 inflammatory markers, 10 showed significant associations with composite pain scores after controlling for covariates and multiple comparisons. (C) Significant linear associations were also observed between 7 of the 14 inflammatory markers and incident depression after controlling for numerous covariates and multiple comparisons. The size of the bars and the internal center represent mean HRs. (D) Mediation analyses showed that six of these seven inflammatory markers significantly and partially mediated the prospective association between composite pain scores and depression incidence while controlling for numerous covariates and multiple comparisons. Dots indicates mean HRs; vertical and horizontal lines indicate 95% CI. Path thickness indicates the strength of associations, and numerical values for the largest and smallest effect sizes are provided for reference.