Genetic predisposition to inflammation and psychopathology: A transdiagnostic network analysis

Although low-grade inflammatory processes have traditionally been studied in affective disorders, they are increasingly recognized as relevant across diagnostic categories. Genetic predisposition and environmental exposures such as childhood trauma (CT) may influence inflammation and shape vulnerability to psychopathology. Understanding how genetic predisposition for inflammation relates to specific symptom dimensions may clarify biological mechanisms underlying psychopathology. In N = 1790 individuals from the Marburg-Münster Affective Disorders Cohort Study (MACS), including patients with affective, anxiety, and psychotic disorders, as well as healthy controls, five transdiagnostic psychopathological syndrome factors were derived using factor analysis of clinical ratings. Polygenic scores (PGS) for circulating tumor necrosis factor TNF-α, interleukin IL-6, IL-10, and CRP were computed to indicate genetic predisposition to low-grade inflammation. Using network analyses, associations between inflammatory PGS and psychopathological syndrome factors were estimated while adjusting for age, sex, and BMI and including CT as a potential moderator. Six direct PGS-syndrome associations emerged, all with small but stable effect sizes. IL-6 PGS had the broadest connectivity, showing negative associations with increased appetite, paranoid-hallucinatory syndrome, and depression, as well as a positive association with negative syndrome. It also had the highest bridging centrality. IL-10 PGS was connected to negative and paranoid hallucinatory syndromes. These associations were largely independent of diagnosis and CT exposure. Integrating inflammatory genetic predisposition into networks of transdiagnostic symptom dimensions reveals small but consistent links between immune-related genetic risk and psychopathology, highlighting shared and distinct immunological pathways across psychiatric disorders.