Examining whether inflammation mediates effects of genetic risk and trauma on psychopathology.

Background: Longitudinal studies have revealed that raised levels of inflammatory markers and trauma in childhood are associated with psychopathology in adulthood.

Aims: To examine whether inflammation in childhood mediates the effects of genetic risk and trauma on psychopathology in early adulthood.

Method: Measures of trauma exposure, inflammation and psychopathology were collected from the Avon Longitudinal Study of Parents and Children. Exposure to trauma was measured from 5 to 11 years of age; C-reactive protein and interleukin-6 levels were measured at 9 years; and depression, anxiety disorders, negative symptoms and psychotic experiences were assessed at 24 years. Polygenic risk scores (PRSs) were created for schizophrenia, depression, anxiety and psychotic experiences. Mediation analyses were conducted using imputed data (N: 7859 to 8700) to investigate whether inflammation mediated the associations of genetic risk and childhood trauma with psychopathology.

Results: Most psychiatric PRSs were associated with multiple psychopathological outcomes in adulthood, with the exception of the PRS for psychotic experiences. Childhood trauma was associated with all psychopathology. However, there was no strong evidence that inflammatory markers in childhood mediated associations among PRSs, trauma and psychopathology. Sensitivity analyses using outcomes from age 18 and PRSs based on single-nucleotide polymorphisms that met more stringent standards of evidence of association gave results consistent with those of our primary analyses.

Conclusions: We found little evidence that interleukin-6 or C-reactive protein mediated the pathway between genetic liability for psychiatric phenotypes or trauma and subsequent psychopathology. Longitudinal investigation of other inflammatory and non-inflammatory pathways is required to identify modifiable targets and inform novel treatment strategies for individuals at genetic or trauma-related risk of psychiatric illness.