Role of inflammation in depressive and anxiety disorders, affect, and cognition: genetic and non-genetic findings in the lifelines cohort study

Abstract

Inflammation is associated with a range of neuropsychiatric symptoms, but the issue of causality remains unclear. We used complementary non-genetic, genetic risk score (GRS), and Mendelian randomization (MR) analyses to examine whether inflammatory markers are associated with affect, depressive and anxiety disorders, and cognition. We tested in ≈55,098 (59% female) individuals from the Dutch Lifelines cohort the concurrent/prospective associations of C-reactive protein (CRP) with: depressive and anxiety disorders; positive/negative affect; and attention, psychomotor speed, episodic memory, and executive functioning at baseline and a follow-up assessment occurring 3.91 years later (SD = 1.21). Additionally, we examined the association between inflammatory GRSs (CRP, interleukin-6 [IL-6], IL-6 receptor [IL-6R and soluble IL-6R (sIL-6R)], glycoprotein acetyls [GlycA]) on these same outcomes (N_min = 35,300; N_max = 57,946), followed by MR analysis examining evidence of causality of CRP on outcomes (N_min=22,154; N_max = 23,268). In non-genetic analyses, higher CRP was associated with depressive disorder, lower positive/higher negative affect, and worse executive function, attention, and psychomotor speed after adjusting for potential confounders. In genetic analyses, CRP_GRS was associated with any anxiety disorder (β = 0.002, p = 0.037) whereas GlycA_GRS was associated with major depressive disorder (β = 0.001, p = 0.036). Both CRP_GRS (β = 0.006, p = 0.035) and GlycA_GRS (β = 0.006, p = 0.049) were associated with greater negative affect. Inflammatory GRSs were not associated with cognition, except sIL-6R_GRS which was associated with poorer memory (β = -0.009, p = 0.018). There was a non-significant CRP-anxiety association using MR (β = 0.12; p = 0.054). Genetic and non-genetic analyses provide consistent evidence for an association between CRP and negative affect. These results suggest that inflammation may impact a broad range of trans-diagnostic affective symptoms.

Fig. 1

Associations of genetic risk scores for inflammatory markers with mood, anxiety disorders and positive and negative affect scores.

Fig. 2

Associations of genetic risk scores for inflammatory markers with cognitive task performance.

Fig. 3. Visualization of the overall pattern of results for CRP in the cohort and genetic analyses.

Arrows indicate direction of effect. Solid arrows (p < 0.05); dashed arrows (p > 0.05). Positive arrows = increased liability to mood and anxiety disorders/affect and better cognitive performance, except for reaction time (RT) measures where positive score = higher RT (i.e., slower response). All psychiatric disorders are from the baseline assessment where sample size is largest. Non-genetic results = adjusted analyses.