Association of DNA methylation marks in the stress response regulating gene KITLG to schizophrenia and bipolar disorder

Abstract

Background: Transcriptional regulation of the KITLG gene by DNA methylation marks at cg27512205 is associated with cortisol stress response in healthy controls and early exposure to childhood adversities. Compelling evidence shows a higher prevalence of childhood adversities in psychotic disorders, but what the role of this methylation mark is in bipolar disorder and schizophrenia is not clear. Methods: We investigated the association of KITLG methylation to schizophrenia and bipolar disorder and the relationship to childhood adversities in whole blood DNA of a sample of 50 patients with bipolar disorder, 15 with schizophrenia and 91 healthy controls. To further tie KITLG function to stress response regulation we analyses the response of KITLG expression to dexamethasone exposure in vitro using 4 human fibroblasts cultures. Results:KITLG methylation was significantly different between the diagnostics groups (F(187,2) = 22.0, p < 0.001). KITLG methylation was lower in bipolar disorder patients (B = −0.33, p < 0.001) and schizophrenia patients (B = −0.33, p < 0.001) also after adjustment for increased KITLG methylation related to childhood adversities in these patient groups (BP; B = 0.009, p = 0.003, Scz; B = 0.012, p = 0.004). Dexamethasone exposure lead to a 50 percent reduction of KITLG expression (FC = 0.45). Conclusions: The results shed new light on the relationship between epigenetic modifications associated with childhood adversities and increased rates of psychotic disorders. The results are consistent with a model whereby failure to increase KITLG methylation in response to childhood adversities leads to maladaptive epigenetic regulation of the stress response in psychotic disorders Houtepen et al. (2016).