Structural brain correlates of serum and epigenetic markers of inflammation in major depressive disorder

Inflammatory processes are implicated in the aetiology of Major Depressive Disorder (MDD); however, the relationship between peripheral inflammation, brain structure and depression remains unclear, partly due to complexities around the use of acute/phasic inflammatory biomarkers. Here, we report the first large-scale study of both serological and methylomic signatures of CRP (considered to represent acute and chronic measures of inflammation respectively) and their associations with depression status/symptoms, and structural neuroimaging phenotypes (T1 and diffusion MRI) in a large community-based sample (Generation Scotland; N MDD cases =271, N controls =609). Serum-CRP was associated with overall MDD severity, and specifically with current somatic symptoms- general interest (β= 0.145, P FDR = 6×10-4) and energy levels (β= 0.101, P FDR = 0.027), along with reduced entorhinal cortex thickness (β= -0.095, P FDR = 0.037). DNAm CRP was significantly associated with reduced global grey matter/cortical volume and widespread reductions in integrity of 16/24 white matter tracts (with greatest regional effects in the external and internal capsules, β FA =- -0.12 to -0.14). In general, the methylation-based measures showed stronger associations with imaging metrics than serum-based CRP measures (βaverage = -0.15 versus βaverage = 0.01 respectively). These findings provide evidence for central effects of peripheral inflammation from both serological and epigenetic markers of inflammation, including in brain regions previously implicated in depression. This suggests that these imaging measures may be involved in the relationship between peripheral inflammation and somatic/depressive symptoms. Notably, greater effects on brain morphology were seen for methylation-based rather than serum-based measures of inflammation, indicating the importance of such measures for future studies.