Differential methylation of OPRK1 in borderline personality disorder is associated with childhood trauma

Abstract

According to a growing body of neurobiological evidence, the core symptoms of borderline personality disorder (BPD) may be linked to an opioidergic imbalance between the hedonic and stimulatory activity of mu opioid receptors (MOR) and the reward system inhibiting effects of kappa opioid receptors (KOR). Childhood trauma (CT), which is etiologically relevant to BPD, is also likely to lead to epigenetic and neurobiological adaptations by extensive activation of the stress and endogenous opioid systems. In this study, we investigated the methylation differences in the promoter of the KOR gene (OPRK1) in subjects with BPD (N = 47) and healthy controls (N = 48). Comparing the average methylation rates of regulatorily relevant subregions (specified regions CGI-1, CGI-2, EH1), we found no differences between BPD and HC. Analyzing individual CG nucleotides (N = 175), we found eight differentially methylated CG sites, all of which were less methylated in BPD, with five showing highly interrelated methylation rates. This differentially methylated region (DMR) was found on the falling slope (5') of the promoter methylation gap, whose effect is enhanced by the DMR hypomethylation in BPD. A dimensional assessment of the correlation between disease severity and DMR methylation rate revealed DMR hypomethylation to be negatively associated with BPD symptom severity (measured by BSL-23). Finally, analyzing the influence of CT on DMR methylation, we found DMR hypomethylation to correlate with physical and emotional neglect in childhood (quantified by CTQ). Thus, the newly identified DMR may be a biomarker of the risks caused by CT, which likely epigenetically contribute to the development of BPD.

Fig. 1. Localization of studied gene regions in OPRK1.

a Gene structure of OPRK1 and covered 10 kb-target section, sequenced in this study. b Localization of a priori specified functional gene regions EH1, CGI-1 and CGI-2. c Localization of in BPD differentially methylated CG sites and DMR (CG34-CG38), respectively.

Fig. 2. Mean methylation rates of individual CG nucleotides within the promoter region of OPRK1 (subregion chr8:53250000-53253000) and localization of CG163 and DMR (CG34-CG38), which are more poorly methylated in BPD.

Both the new DMR localizing within the falling slope (5’) and CG163 within the rising slope (3’) of the methylation gap strengthen the effect of the promoter hypomethylation in BPD. Detail: enlarged view of the clustering CG34-38, each hypomethylated in BPD, building the DMR. Red dots: BPD, blue dots: HC.