The significance of the EOS in borderline personality disorder: epigenetic alterations in OPRM1, OPRD1, OPRK1, and OPRL1

The significance of the EOS in borderline personality disorder: epigenetic alterations in OPRM1, OPRD1, OPRK1, and OPRL1 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article The significance of the EOS in borderline personality disorder: epigenetic alterations in OPRM1, OPRD1, OPRK1, and OPRL1 Dorothee Gescher, Peter Vavra, Denny Schanze, Martin Zenker, Stephanie Witt, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7489711/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract The high relevance of childhood trauma in the etiology of borderline personality disorder (BPD) is likely due to epigenetic adaptations associated with exhaustive stress early in life. There is increasing evidence that imbalances in the endogenous opioid system (EOS), which is tightly linked to the stress system, underlie part of the BPD pathophysiology. The aim of this study was to first investigate DNA methylation differences in the promoter regions of the opioid receptor (OR) genes OPRM1 , OPRD1 , and OPRL1 in subjects with BPD (N = 47) and in healthy controls (N = 48). Analyzing individual CG nucleotides (N = 1233), we identified differentially methylated CG sites in OPRM1 (N = 3), OPRD1 (N = 4), and OPRL1 (N = 15). Our findings indicate an increased transcription of these less methylated genes. Further, to study the OR system in its entirety, we analyzed the methylation rate correlation of the CG sites identified to have been differentially methylated in OPRM1 , OPRD1 , and OPRL1 , including existing data of OPRK1 . Distinct associations of the methylation rates were found to form intragenic and intergenic methylation clusters, indicating the impact of methylation alterations on the OR system, and the concurrent activation and mutual regulation of ORs. Together, our findings suggest altered transcription of all OR genes, which likely leads to EOS hypersensitivity and dysregulation, resulting in an unbalanced hyperactivation of inhibitory and disinhibitory effects that may account for the core BPD symptoms. In addition, the observed BPD-related methylation changes in OR genes and their partial synchronization support the role of the EOS in BPD pathobiology. Biological sciences/Genetics Biological sciences/Molecular biology Health sciences/Diseases/Psychiatric disorders Figures Figure 1 Figure 2 INTRODUCTION Affecting between 0.7 and 2.7% of the general adult population [ 1 , 2 ], borderline personality disorder (BPD), is one of the most challenging mental conditions. Over the past few decades there has been a significant amount of research on the subject, focusing on the diagnostic classification of BPD, its etiology and neurobiological underpinnings, course, and the efficacy and sustainability of existing treatment strategies [ 3 , 4 ]. It has been hypothesized that brain and personality development is influenced by the interaction of genetic factors and stressful experiences in childhood [ 5 – 7 ]. A recent genome-wide association study on BPD, the largest of its kind, has identified 11 significant genomic loci and nine risk genes, and a high genetic overlap with other mental disorders, especially PTSD, depressive disorder and ADHD [ 8 ]. Environmental factors such as early childhood adversity, including emotional and physical neglect or abuse and sexual violence, are assumed to modulate gene expression, but epigenetic studies on BPD have so far yielded limited and inconsistent results [ 9 , 10 ]. Dysfunctions of several neurobiological systems, including serotoninergic, dopaminergic, and other neurotransmitter systems such as oxytocin and the hypothalamic-pituitary-adrenal (HPA) axis [ 4 ], have been discussed in the context of neuroendocrine alterations. There is growing evidence that imbalances in the endogenous opioid system (EOS), which is closely linked to the stress system, partly constitute the BPD pathophysiology [ 11 ]. As a complex neuro-modulatory system, the EOS includes the endogenous opioid neuropeptides beta-endorphins (BE), enkephalins (ENK), dynorphins (DYN), and nociceptin/orphanin FQ (N/OFQ), which act with varying affinity on four groups of receptors: mu (MOR), delta (DOR), kappa (KOR), and nociceptin (NOP) opioid receptors. Together, they play a major role in stress responses, pain modulation, mood and motor regulation, reward processes, and control many other physiological aspects such as respiration, and gastrointestinal, endocrine and immunological functions [ 12 ]. According to the “EOS theory of BPD”, inadequate availability of endogenous opioids, or the altered sensitivity of opioid receptors (OR), leads to functional dysregulation. Negative affectivity, feelings of emptiness and disconnection/loneliness, particularly in stressful situations, may thus be a result of an opioid deficiency leading to dysfunctional behavior such as self-harm, risk-taking behavior, overeating, and drug use aiming to upregulate and restore sufficient EOS activity [ 13 , 14 ]. In support of this theory, studies have found reduced BE in CSF and plasma levels in individuals with non-suicidal self-injury (NSSI) [ 14 – 16 ], and individual increase of BE saliva levels immediately after NSSI [ 17 ]. On the other hand, Kao and colleagues’ longitudinal treatment study involving adolescents did not find significant associations of BE plasma levels with NSSI or BPD-symptoms but with depression [ 18 ]. A PET study using [(11)C]carfentanil for in vivo quantification of MOR availability provided further evidence by showing elevated baseline receptor concentrations in the amygdala and the nucleus accumbens in female BPD patients, along with increased excitability of the EOS in response to a negative affective stimulus [ 19 ]. According to the authors of this study, the increased receptor expression was an adaptation to insufficient basal opioid activity. Similarly, Bresin and Gorden discussed the pathophysiology of NSSI as a triad of low basal endogenous opioids, their release through NSSI, and the affect-regulating effect of their release [ 20 ]. To date, very few studies on endogenous opioid deficiency have covered the full range of BPS symptoms, focusing instead on aspects such as NSSI or depression independent of BPD. With disparate study designs, they have yielded somewhat inconsistent results. For example, pain sensitivity, which is also modulated by BE, has not been found to be associated with basal BE levels in individuals with NSSI [ 15 , 16 ]. Further indications of the impact of the EOS on BPD symptomatology emerge from treatment studies with opioid antagonists, which have been shown to reduce BPD-associated symptoms [ 21 , 22 ] such as NSSI [ 22 , 23 ], binge eating [ 22 ], suicidality [ 24 ] and dissociation [25.26]. By inordinately activating the HPA axis early in life, childhood trauma, which is closely related to the development of BPD [ 27 , 28 ], can lead to genome-wide epigenetic modification of gene transcription, particularly in the gene systems including NR3C1, CRF, AVP [ 29 – 31 ]. The HPA axis is closely linked to the EOS with CRF and dynorphin being co-released in stress and both leading to HPA activation involving all ORs [ 32 , 33 ]. Recently, we have found a differentially methylated region in the KOR gene ( ORK1) that was hypomethylated in BPD and associated with physical and emotional neglect in childhood [ 34 ]. In line with this, the expression of KOR and DYN has been found to be increased in subjects with NSSI [ 35 ]. In light of this confluence and the findings mentioned above, our study is the first to analyze epigenetic signatures in BPD within the full range of the endogenous opioid receptor (OR) system and evaluate the core sensitivity of the EOS. Based on our hypothesis that BPD subjects exhibit methylation alterations in all OR genes, which may interact with one another, we studied the methylation rates of functionally relevant parts of the OR genes ( OPRM1 , OPRD1 , OPRK1 and OPRL1 ) in a well-characterized cohort of 47 unmedicated females with BPD and compared them with 48 healthy age-matched female controls. METHODS Samples Biosamples were derived from subjects who took part in different studies within the DFG-funded Clinical Research Unit 256 (KFO256 [ 36 ]) and who were recruited between 2012 and 2014 at the Central Institute of Mental Health Mannheim, Germany. The relevant studies were approved by the appropriate Ethics Committee. All participants provided written informed consent including epigenetic analyses. In this case-control study, we selected 47 medication-free, non-smoking female patients with a current diagnosis of BPD ( M age =25.21 years, SD age =4.21; M BMI =24.28 kg/m 2 , SD BMI =5.58) and 48 female, non-smoking healthy subjects ( M age =24.71 years, SD age =3.96; M BMI =22.88 kg/m 2 , SD BM =3.79). The general exclusion criteria comprised neurological disorders, current alcohol or drug abuse or dependence in the last 12 months, lifetime diagnosis of schizophrenia, schizoaffective or bipolar disorder, severe medical illness, including cardiac dysregulations, and use of psychotropic medication. The diagnostic of BPD was confirmed by means of the International Personality Disorder Examination (IPDE [ 37 ]) and the Structured Clinical Interview for the DSM-IV (SCID [ 38 ]) was used for the assessment of the exclusion criteria. Childhood adverse experience was measured using the Childhood Trauma Questionnaire (CTQ [ 39 ]). DNA methylation analysis The analyses were performed on isolated genomic DNA from whole blood samples of each subject. DNA was sheared into fragments of 150–200 bp by focused-ultrasonic fragmentation using the Covaris S220 sonication system (Covaris Ltd, Brighton, GB). DNA methylation was analyzed via multiplex bisulfide PCR sequencing in accordance with the manufacturer’s instructions without modification (SureSelect XT Methyl-Seq Target Enrichment System for Illumina Multiplexed Sequencing, Agilent Technologies Inc., Santa Clara, CA, USA). Sequencing was done on an Illumina MiSeq ™ System (2 x 150-bp paired-end) (Illumina Inc., San Diego, CA, USA) followed by demultiplexing and quality control for the generated reads (Q30 > 90%). Target regions of investigated genes For the designing of target regions in the investigated genes, localization of exons, translation start site (TLS), promoter and known gene regulation elements were identified using UCSC ( https://genome.ucsc.edu ) and ensembl genome browser ( https://www.ensembl.org ) databases. All gene localizations in this article refer to hg38. We analyzed selected regions of the genes OPRM1 (chr6:154034307–154044307 (10 kb); 100 CG), OPDR1 (chr1:28,807141-28817141 (10 kb), and chr1:28852953–28862953 (10 kb); 495 CG), OPRL1 (chr20:64074617–64085617 (11 kb), and chr20:64087687–64097687 (10 kb); 638 CG). In the analysis of intergenic correlations within the EOS, we included recently published methylation rates of OPRK1 [ 34 ], enabling us to analyze the interaction of the complete receptor system. These specified regions constituted part of a customized panel (SureSelect XT targeted methyl panel, Agilent Technologies, Inc., CA, USA). Bioinformatics The generated fastq files were quality-checked by means of fastqc v0.11.9 [ 40 ]. Adaptors were trimmed using TrimGalore v0.6.7 [ 41 ] and subsequently analyzed with Bismark v0.23.1 [ 42 ] using the embl hg38 primary assembly DNA (GenBank Assembly ID GCA_000001405.28) for reference genome to extract the number of converted and unconverted cytosine for each CG in the targeted genomic region. Statistical analyses were programed and carried out with R (version 4.5.1; R Core Team, 2025). All cytosines of CG’s with less than 25 reads or less than 10 remaining samples per group were excluded from calculations. Statistical analysis We assessed single CG sites’ methylation rates for the entire sequenced gene regions of OPRM1 , OPRD1 , and OPRL1 . To account for different read counts of individual CG’s, we performed logistic regression for all analyses, controlling age and BMI, which resulted in 83 ( OPRM1 ), 353 ( OPRD1 ), and 517 ( OPRL1 ) individual CG sites with enough data. The significance test was performed with the t-value of the difference in log-odds between BPD and HC. To control multiple comparisons, we set the significance level at p .05 with an FDR correction for multiple testing [ 43 ]. Based on the results of this analysis, we assessed the methylation rate consistency of these in differently methylated CG sites by calculating correlations across participants, controlling for age and BMI. Here we included existing own methylation data of OPRK1 , which originate from the same subjects and the same methylation analysis, and were calculated equally [ 34 ]. We first investigated correlations within a gene and then between the genes studied using Pearsons’s correlation coefficients. RESULTS Methylation rates of 22 distinct CG sites within the targeted regions of OPRM1 , OPRD1 , and OPRL1 are different in BPD Within the total of 83 analyzed CG sites across the OPRM1 gene, we found 3 CG sites to be methylated significantly differently between BPD and HC. OPRM1-CG16 was less methylated in BPD, and OPRM1-CG52 and -CG62 were hypermethylated in BPD. As the most upstream site, CG16 is located directly 5’ before the promoter, whereas OPRM1-CG52 and OPRM1-CG62 are located within exon 1 and intron 1. As regards the OPRD1 gene, we found 4 CG sites within the total of 453 analyzed CG sites to be differently methylated between BPD and HC. OPRD1-CG150 is located within intron 1 and was hypermethylated in BPD, the other three significantly differently methylated CG (OPRD1-CG324/-CG331/-CG332) are located within intron 2 close to the 5’ end of exon 3. In the analyzed regions of OPRL1 , we found 15 CG sites being differently methylated in BPD. Apart from OPRL1-CG8, which is in the 5’region of the gene, OPRL1-CG155, -CG156, -CG165, -CG186, -CG308, -CG319, and -CG331 are located in the intron 1. There, they are situated inside functional regions such as enhancer sequences (OPRL1-CG155/-CG156/-CG165), the second promoter (OPRL1-CG308/-CG319/-CG331). All of these were less methylated in BPD. Further differentially methylated CG sites were OPRL1-CG406, located at the end of intron 1 (230 bp upstream of exon 2), which was hypermethylated in BPD, and six CG sites in intron 3: OPRL1-CG462 and -CG463, less methylated in BPD, located consecutively, OPRL1-CG502, hypermethylated in BPD, and -CG508, -CG509, and -CG511, all less methylated in BPD, located closely to one another and before exon 4. Table 1 and Fig. 1 summarize the results and locations within the genes. Table 1 Methylation rates of individual CG sites within OPRM1 , OPRD1 , OPRK1 , and OPRL1 that differ significantly between subjects with BPD and HC, significance level at p .05 with an FDR-correction for multiple testing (Benjamini and Hochberg). *CG related to E3 start, **CG related to TLS, # Gescher et al. [ 34 ] CG-ID CG related to TLS position related to TLS gene region chr position BPD methylation rate [%] HC methylation rate [%] Odds- Ratio t-value p -value (adjusted) OPRM1-CG16 -23 -488 P1 6 154039058 26.77 29.74 1.171 5.279 0.000 OPRM1-CG52 14 206 E1 6 154039751 17.38 15.91 0.866 -3.288 0.039 OPRM1-CG62 24 429 I1 6 154039974 43.02 40.33 0.896 -3.192 0.039 OPRD1-CG150 86 1805 I1 1 28814189 92.44 90.54 0.759 -4.150 0.004 OPRD1-CG324 -15* 49735 I2 1 28862119 57.14 65.83 1.509 5.103 0.000 OPRD1-CG331 -8* 50071 I2 1 28862455 76.48 78.79 1.126 3.537 0.036 OPRD1-CG332 -7* 50082 I2 1 28862466 86.85 89.12 1.244 4.986 0.000 OPRK1-CG17 # -106 -3478 upstream 8 53254514 81.71 81.00 0.898 10.186 0.000 OPRK1-CG34 # -89 -1162 upstream 8 53252198 33.36 36.32 1.134 3.560 0.016 OPRK1-CG35 # -88 -1116 upstream 8 53252152 54.86 55.99 1.098 3.118 0.038 OPRK1-CG36 # -87 -1101 upstream 8 53252137 60.75 62.54 1.118 3.189 0.034 OPRK1-CG37 # -86 -993 upstream 8 53252029 66.54 68.67 1.101 3.721 0.016 OPRK1-CG38 # -85 -978 upstream 8 53252014 53.29 55.23 1.092 3.191 0.034 OPRK1-CG144 # 41 512 I2 8 53250525 54.44 56.57 1.102 3.564 0.016 OPRK1-CG156 # 53 2508 I2 8 53248529 91.77 94.98 1.874 -3.347 0.027 OPRL1-CG8 -182** -17451 5' region 20 64075271 90.34 92.10 1.211 3.669 0.014 OPRL1-CG155 38** -12114 I1 20 64080608 24.67 26.60 1.108 3.234 0.042 OPRL1-CG156 39** -12110 I1 20 64080612 29.00 31.44 1.119 3.720 0.014 OPRL1-CG165 48** -11772 I1 20 64080950 33.78 36.80 1.140 3.584 0.018 OPRL1-CG186 69** -10597 I1 20 64082125 23.73 26.77 1.173 4.878 0.000 OPRL1-CG308 230** -8132 I1 20 64084590 34.58 36.93 1.110 3.291 0.039 OPRL1-CG319 245** -7773 I1 20 64084949 16.22 20.21 1.309 3.275 0.039 OPRL1-CG331 257** -7629 I1 20 64085093 58.73 62.07 1.153 3.663 0.014 OPRL1-CG406 -36 -972 I1 20 64091750 86.45 84.87 0.857 -3.979 0.006 OPRL1-CG462 21 625 I3 20 64093346 67.48 76.92 1.513 10.276 0.000 OPRL1-CG463 22 630 I3 20 64093351 80.60 83.18 1.176 3.436 0.028 OPRL1-CG502 64 3427 I3 20 64096148 86.34 84.59 0.869 -3.376 0.032 OPRL1-CG508 70 3842 I3 20 64096563 52.61 54.31 1.191 6.998 0.000 OPRL1-CG509 71 3906 I3 20 64096627 87.83 91.71 1.636 9.871 0.000 OPRL1-CG511 73 3967 I3 20 64096688 88.73 92.13 1.646 7.091 0.000 Correlation analyses of differentially methylated CG sites in OPRM1 , OPRD1 , OPRK1, and OPRL1 Significant intragenic correlations between CG sites methylated differently in BPD We found no correlations for OPRM1 within the investigated CG sites, which were significantly altered in BPD. Within the four differentially methylated CG sites in OPRD1 , we found only OPRD1-CG331 and -CG332 to be highly positively correlated with each other (r = .6663, p < .0001 ). The methylation rate in OPRK1 showed a positive correlation at the adjacent sites OPRK1-CG36/-CG37/-CG38, and -CG144, and, except for -CG37, also with -CG35. In OPRL1 , OPRL1-CG156, -CG165, -CG186, -CG308, -CG329 and -CG331 were positively correlated with one another, and negatively with CG502, thus forming a cluster of similarly and oppositely deviating methylation in BPD. We summarized all statistical indicators of the significant intergenic correlations in Table 2 . Table 2 Correlation between methylation rates of CG sites in OPRM1 , OPRD1, OPRK1 , and OPRL1 that are differentially methylated in BPD vs. HC, controlled for age and BMI (Pearson's correlation coefficients). Only significant correlations are depicted. r ( p ) OPRM1-CG16 OPRM1-CG52 OPRM1-CG62 OPRD1-CG150 OPRD1-CG324 OPRD1-CG331 OPRD1-CG332 OPRK1-CG17 OPRK1-CG34 OPRK1-CG35 OPRK1-CG36 OPRK1-CG37 OPRK1-CG38 OPRK1-CG144 OPRK1-CG156 OPRL1-CG8 OPRL1-CG155 OPRL1-CG156 OPRL1-CG165 OPRL1-CG186 OPRL1-CG308 OPRL1-CG319 OPRL1-CG331 OPRL1-CG406 OPRL1-CG462 OPRL1-CG463 OPRL1-CG502 OPRL1-CG508 OPRL1-CG509 OPRL1-CG511 OPRM1-CG16 1 (N/A) 0.059 (0.578) 0.114 (0.275) -0.049 (0.641) 0.187 (0.114) 0.16 (0.126) 0.192 (0.065) -0.084 (0.426) 0.141 (0.178) -0.009 (0.933) -0.038 (0.721) -0.094 (0.369) -0.082 (0.434) -0.043 (0.683) -0.11 (0.296) -0.026 (0.804) -0.135 (0.196) -0.152 (0.145) -0.048 (0.647) -0.134 (0.202) -0.112 (0.284) 0.038 (0.721) 0.113 (0.283) -0.026 (0.802) -0.093 (0.377) 0.090 (0.394) 0.043 (0.683) -0.054 (0.606) 0.245 (0.018) 0.234 (0.024) OPRM1-CG52 1 (N/A) 0.103 (0.326) 0.055 (0.605) 0.098 (0.41) -0.077 (0.465) -0.097 (0.356) 0.236 (0.023) 0.107 (0.309) -0.189 (0.07) -0.026 (0.808) 0.194 (0.063) 0.047 (0.652) 0.038 (0.72) -0.004 (0.967) 0.002 (0.981) 0.085 (0.417) 0.156 (0.136) 0.076 (0.471) 0.079 (0.451) -0.036 (0.729) -0.027 (0.802) -0.052 (0.621) 0.122 (0.246) -0.149 (0.156) -0.015 (0.886) 0.118 (0.258) -0.017 (0.869) 0.111 (0.288) 0.119 (0.255) OPRM1-CG62 1 (N/A) 0.032 (0.765) 0.080 (0.499) 0.146 (0.162) 0.060 (0.566) -0.026 (0.806) 0.153 (0.144) -0.098 (0.349) -0.224 (0.031) -0.106 (0.311) -0.161 (0.124) -0.024 (0.823) -0.059 (0.577) 0.117 (0.265) -0.162 (0.12) -0.132 (0.206) -0.202 (0.053) -0.176 (0.0911) -0.064 (0.543) -0.078 (0.464) 0.000 (0.998) 0.007 (0.949) -0.112 (0.287) -0.090 (0.394) 0.237 (0.022) -0.026 (0.803) 0.321 (0.002) 0.3 (0.004) OPRD1-CG150 1 (N/A) -0.127 (0.283) -0.018 (0.867) -0.022 (0.837) -0.007 (0.948) 0.021 (0.846) -0.053 (0.614) -0.012 (0.908) 0.21 (0.044) 0.116 (0.271) 0.132 (0.211) -0.033 (0.755) 0.063 (0.549) 0.111 (0.291) -0.045 (0.673) 0.008 (0.939) 0.063 (0.553) 0.081 (0.441) -0.085 (0.426) -0.030 (0.774) 0.15 (0.155) -0.013 (0.899) 0.064 (0.542) 0.171 (0.104) -0.151 (0.15) 0.001 (0.989) -0.001 (0.992) OPRD1-CG324 1 (N/A) -0.066 (0.578) 0.037 (0.756) 0.12 (0.313) 0.178 (0.132) 0.073 (0.537) 0.2 (0.091) 0.117 (0.326) 0.023 (0.846) 0.051 (0.666) 0.1 (0.399) -0.048 (0.686) 0.105 (0.375) 0.075 (0.527) 0.064 (0.592) 0.129 (0.275) -0.006 (0.963) 0.152 (0.199) 0.144 (0.223) -0.087 (0.465) -0.097 (0.414) -0.034 (0.777) 0.000 (0.998) 0.073 (0.54) 0.21 (0.074) 0.205 (0.081) OPRD1-CG331 1 (N/A) 0.657 (< 0.001) 0.181 (0.083) -0.083 (0.431) -0.042 (0.689) 0.142 (0.173) 0.025 (0.813) 0.143 (0.173) 0.233 (0.0247) 0.298 (0.004) 0.381 (< 0.001) -0.292 (0.005) -0.31 (0.003) -0.126 (0.231) -0.177 (0.0888) -0.198 (0.0573) -0.08 (0.455) -0.036 (0.735) 0.063 (0.551) 0.038 (0.718) 0.24 (0.022) 0.3 (0.004) 0.208 (0.046) -0.062 (0.556) -0.068 (0.519) OPRD1-CG332 1 (N/A) 0.013 (0.905) 0.119 (0.254) 0.073 (0.489) 0.17 (0.103) 0.176 (0.091) 0.241 (0.02) 0.156 (0.135) 0.206 (0.048) 0.43 (< 0.001) -0.123 (0.239) -0.158 (0.131) -0.045 (0.674) -0.058 (0.582) -0.047 (0.658) -0.024 (0.821) 0.011 (0.915) -0.008 (0.937) 0.103 (0.329) 0.237 (0.023) 0.325 (0.002) 0.092 (0.387) 0.079 (0.449) 0.061 (0.564) OPRK1-CG17 1 (N/A) -0.132 (0.206) -0.079 (0.451) -0.145 (0.166) 0.161 (0.122) 0.142 (0.174) 0.091 (0.384) 0.64 (< 0.001) 0.032 (0.765) -0.102 (0.329) -0.069 (0.512) 0.060 (0.569) 0.014 (0.897) 0.016 (0.883) -0.017 (0.876) 0.000 (0.999) -0.025 (0.813) -0.113 (0.284) 0.019 (0.858) 0.048 (0.648) 0.077 (0.461) -0.003 (0.98) 0.007 (0.945) OPRK1-CG34 1 (N/A) 0.12 (0.251) 0.126 (0.228) 0.201 (0.053) 0.26 (0.012) 0.154 (0.141) -0.125 (0.231) 0.227 (0.029) 0.166 (0.111) 0.142 (0.174) 0.009 (0.932) 0.1 (0.34) 0.13 (0.214) 0.211 (0.046) -0.024 (0.821) -0.034 (0.744) 0.032 (0.764) 0.047 (0.654) 0.016 (0.878) -0.129 (0.218) 0.075 (0.476) 0.086 (0.413) OPRK1-CG35 1 (N/A) 0.4 (< 0.001) 0.155 (0.139) 0.318 (0.002) 0.279 (0.007) 0.073 (0.484) 0.064 (0.542) 0.18 (0.085) 0.187 (0.072) 0.212 (0.042) 0.18 (0.084) 0.175 (0.093) 0.116 (0.276) -0.061 (0.56) -0.054 (0.605) 0.058 (0.58) -0.041 (0.699) -0.166 (0.113) -0.003 (0.978) 0.115 (0.271) 0.145 (0.167) OPRK1-CG36 1 (N/A) 0.395 (< 0.001) 0.459 (< 0.001) 0.405 (< 0.001) 0.006 (0.959) 0.117 (0.266) 0.125 (0.231) 0.167 (0.109) 0.219 (0.036) 0.239 (0.021) 0.043 (0.684) 0.186 (0.08) 0.034 (0.745) -0.004 (0.967) 0.086 (0.417) 0.048 (0.653) -0.035 (0.738) -0.022 (0.838) 0.108 (0.302) 0.116 (0.269) OPRK1-CG37 1 (N/A) 0.681 (< 0.001) 0.464 (< 0.001) 0.163 (0.119) 0.283 (0.006) 0.297 (0.004) 0.314 (0.002) 0.257 (0.013) 0.19 (0.068) 0.31 (0.003) 0.24 (0.023) 0.096 (0.359) 0.089 (0.399) 0.109 (0.302) 0.105 (0.319) -0.002 (0.983) -0.039 (0.715) 0.109 (0.299) 0.092 (0.381) OPRK1-CG38 1 (N/A) 0.508 (< 0.001) 0.176 (0.092) 0.332 (0.001) 0.115 (0.27) 0.129 (0.217) 0.084 (0.427) 0.065 (0.538) 0.092 (0.379) 0.1 (0.348) 0.036 (0.732) -0.020 (0.851) 0.067 (0.526) 0.065 (0.538) 0.021 (0.84) 0.019 (0.86) 0.092 (0.383) 0.088 (0.403) OPRK1-CG144 1 (N/A) 0.164 (0.116) 0.292 (0.004) 0.135 (0.198) 0.115 (0.271) 0.015 (0.891) 0.076 (0.471) 0.066 (0.532) 0.225 (0.033) 0.022 (0.837) -0.050 (0.636) 0.064 (0.545) 0.13 (0.216) 0.059 (0.576) -0.065 (0.533) 0.054 (0.608) 0.052 (0.621) OPRK1-CG156 1 (N/A) 0.23 (0.027) -0.079 (0.452) -0.046 (0.66) 0.124 (0.24) 0.069 (0.512) 0.113 (0.281) 0.047 (0.66) 0.052 (0.619) -0.011 (0.917) -0.13 (0.218) 0.041 (0.701) -0.033 (0.754) 0.148 (0.157) -0.077 (0.464) -0.076 (0.47) OPRL1-CG8 1 (N/A) 0.055 (0.599) 0.023 (0.829) 0.152 (0.147) 0.063 (0.546) 0.234 (0.024) 0.086 (0.419) 0.019 (0.854) 0.099 (0.344) 0.094 (0.375) 0.305 (0.003) 0.100 (0.342) 0.050 (0.632) 0.085 (0.418) 0.079 (0.452) OPRL1-CG155 1 (N/A) 0.877 (< 0.001) 0.653 (< 0.001) 0.773 (< 0.001) 0.6 (< 0.001) 0.245 (0.02) 0.262 (0.011) -0.084 (0.426) 0.051 (0.627) 0.141 (0.179) -0.409 (< 0.001) -0.11 (0.293) 0.029 (0.786) 0.018 (0.865) OPRL1-CG156 1 (N/A) 0.646 (< 0.001) 0.709 (< 0.001) 0.557 (< 0.001) 0.25 (0.018) 0.199 (0.056) -0.102 (0.328) 0.066 (0.532) 0.040 (0.706) -0.418 (< 0.001) -0.043 (0.68) 0.0471 (0.654) 0.037 (0.729) OPRL1-CG165 1 (N/A) 0.673 (< 0.001) 0.604 (< 0.001) 0.376 (< 0.001) 0.318 (0.002) 0.025 (0.815) 0.071 (0.5) 0.121 (0.251) -0.418 (< 0.001) -0.056 (0.599) 0.114 (0.279) 0.119 (0.258) OPRL1-CG186 1 (N/A) 0.649 (< 0.001) 0.342 (0.001) 0.233 (0.025) -0.047 (0.656) 0.087 (0.408) 0.174 (0.098) -0.496 (< 0.001) -0.077 (0.465) 0.054 (0.606) 0.038 (0.721) OPRL1-CG308 1 (N/A) 0.238 (0.024) 0.201 (0.053) -0.015 (0.887) 0.225 (0.031) 0.156 (0.139) -0.449 (< 0.001) -0.238 (0.022) 0.132 (0.206) 0.106 (0.311) OPRL1-CG319 1 (N/A) 0.335 (0.001) 0.073 (0.492) 0.117 (0.274) 0.0651 (0.542) -0.261 (0.013) -0.155 (0.146) 0.088 (0.41) 0.082 (0.442) OPRL1-CG331 1 (N/A) -0.014 (0.897) 0.029 (0.783) 0.191 (0.069) -0.252 (0.015) -0.178 (0.089) 0.258 (0.013) 0.249 (0.016) OPRL1-CG406 1 (N/A) 0.103 (0.327) 0.259 (0.013) 0.136 (0.194) -0.171 (0.102) 0.003 (0.977) 0.004 (0.969) OPRL1-CG462 1 (N/A) 0.431 (< 0.001) -0.135 (0.2) -0.535 (< 0.001) -0.137 (0.192) -0.152 (0.147) OPRL1-CG463 1 (N/A) -0.037 (0.726) -0.274 (0.008) 0.105 (0.32) 0.092 (0.381) OPRL1-CG502 1 (N/A) 0.265 (0.010) 0.020 (0.848) 0.031 (0.767) OPRL1-CG508 1 (N/A) -0.289 (0.005) -0.274 (0.008) OPRL1-CG509 1 (N/A) 0.991 (< 0.001) OPRL1-CG511 1 (N/A) R Pearson's correlation coefficient, p p -value. Significant intergenic correlations of CG sites methylated differently in BPD Considering all the investigated gene regions, we found individual CG sites of different genes whose methylation rates were correlated. We identified such intergenic correlations between almost all genes, except between OPRM1 and OPRD1 (Fig. 2 ). For example, the methylation rates of two CG sites of both the OPRM1 and the OPRK1 genes were correlated with each other (OPRM1-CG52 with OPRK1-CG17 and OPRM1-CG62 with OPRK1-CG36). Further significant intergenic correlations for OPRM1 were found with CG sites of OPRL1 (OPRM1-CG16 and -CG62 each with OPRL1-CG509 and -CG511), but with none in OPRD1 . In OPRD1 , the methylation rates of OPRD1-CG331 and -CG33, which had a strong positive correlation with each other, correlated positively with 3 CG sites in OPRL1 (OPRL1-CG8/-CG463/-CG502). Also, the methylation rate of OPRD1-CG331 correlated negatively with those of OPRL1-CG155 and -CG156. In addition to the ones described for OPRM1 , the methylation of specific CGs of OPRK1 correlated with selected CGs in OPRL1 and OPRD1 . Notably, the methylation rate of OPRK1-CG37 correlated positively with those of six CGs in OPRL1 (OPRL1-CG8/-CG155/-CG156/-CG165/-CG308/-CG319), five of which are part of the intragenic cluster identified in OPRL1. This results in an extended intergenic methylation cluster that also omits any correlations with OPRM1 . Table 2 summarizes all statistical indicators of the significant intergenic correlations. DISCUSSION In this study, we sought to provide an integrative view of methylation changes in the entire set of OR in BPD as they are all involved in the mediation of stress response [ 33 ] and mutual regulation [ 44 ]. We found methylation alterations in all the genes examined (Table 1 , Fig. 1 ). Their individual significance with respect to gene activity, including that of OPRK1 , is discussed below [ 34 ]. The epigenetic control of OR by promoter methylation has been repeatedly demonstrated [ 45 – 49 ]. Moreover, we found associations between the methylation rates of the CG sites altered in BPD at the OPRM1 , OPRD1 , OPRK1 , and OPRL1 genes, identifying epigenetic interactions or joint activities within the transmitter systems. The results are discussed with respect to a possible link with the core clinical symptoms of BPD. OPRM1 Our results revealed a highly significant hypomethylation in BPD subjects at the 5’ end of the promoter unmethylated domain of OPRM1 (CG16), and hypermethylation of two CG sites downstream at the end of exon 1 (OPRM1-CG52) and the 5’ end of intron 1 (OPRM1-CG62), both located shortly downstream of the promoter region, which is already known to be epigenetically regulated [ 45 – 47 ]. The hypermethylation of CG52 and CG62 in BPD may be more relevant as the methylation downstream of the TSS including the first exon is more crucial for transcription [ 50 ]. The impact of CG52 hypermethylation is further enhanced by its location in an enhancer region, which can interfere with enhancer binding. Conversely, only CG16 is in the promoter region, but is significantly hypomethylated in BPD. Taken together, our results are contradictory and limit a functional analysis of their transcriptional impact. To our knowledge, there is no other epigenetic study on OPRM1 and BPD. Previous studies found a region within the first exon including parts of the promoter region being hypermethylated in patients with alcohol dependence [ 51 ]. Hypermethylation of distinct CGs in this region was also found in patients with opioid dependence or chronic use and could most likely be the result of the drug [ 52 – 55 ]. This assumption is supported by studies that found newborns of mothers who used morphine during pregnancy to exhibit hypermethylation within the OPRM1 promoter and increased withdrawal symptoms after birth [ 56 ]. Interestingly, a significant hypomethylation of 11 consecutive CGs within the OPRM1 promoter region was found in extremely preterm infants in response to and in correlation with neonatal stress exposure [ 57 ]. These findings differ from those obtained in studies on early substance exposure [ 56 , 58 ]. Stress, for example, evokes the release of various transmitters including endogenous opioids, with complex effects on the neural network. They are rapidly metabolized to enable a highly flexible excitatory system. This means that brain amino peptides such as enkephalins are immediately hydrolyzed after release and are degraded by endopeptidases, resulting in the very short half-life of endogenous peptides [ 59 ]. The effect of endogenous opioids on MOR is further limited due to their rapid endocytosis and recycling in the cell through strong coupling of intracellular mechanisms, which prevents tolerance [ 60 ]. Morphine, by contrast, fails to induce receptor endocytosis by binding to MOR, and the resensitization of MOR is impaired, which leads to the aberrantly prolonged signaling that in turn contributes to cellular morphine tolerance [ 61 – 63 ]. Along with the much longer half-life compared to those of endogenous opioids, the different ways in which morphine and several other opioid drugs [ 60 ] work on MORs, including causing adaptive intracellular changes, can help explain why epigenetic changes in opioid use [ 56 , 58 ] are different from those linked to early life stress [ 57 ]. The effects of neonatal stress exposure [ 57 ] with hypomethylation of parts of the OPRM1 promoter are most similar to our findings in BPD, which also align with early stress experiences in the BPD etiology. OPRD1 In the sequences of the DOR gene OPRD1 that we analyzed, we found four CG sites that were differently methylated in BPD. Unlike OPRM1 , we found no methylation alterations in the promoter, exon 1, and an enhancer binding site (EH38E1332550), which are most likely functionally relevant for transcription initiation [ 50 ]. As the most proximal differently methylated CG site, OPRD1-CG150, located in intron 1, was hypermethylated in BPD. Its hypermethylation could contribute to transcriptional stability, since high DNA methylation within the gene body is associated with a higher level of gene expression and transcriptional elongation, and is supposed to protect against interference with the transcription process [ 64 , 65 ]. The other CG sites differently methylated in BPD were found close to one another, immediately 5’ to exon 3, and were all less highly methylated in BPD (OPRD1-CG324/-CG331/-CG332). Nearby, upstream of these, was a distal enhancer binding sequence involved in the control of gene expression (ENSR00000352119). How this interacts with the transcription start site (TSS) or directly modulates the transcription of exon 3 has not been specified in detail. We hypothesize that hypomethylation in this region, as identified in our study, may facilitate the binding of enhancers or other transcription factors. Taken together, our data suggest an increased transcription stability of the gene OPRD1 in BPD. In their study analyzing 12, 25, and 45 CpG sites in the promoter regions of the OPRM1 , OPRD , and OPRK1 genes, Yu et al. found several individual CG sites of OPRD1 and OPRK1 that were more highly methylated in subjects with opioid use disorder (OUD), but not after Bonferroni correction [ 49 ]. Their nominal results seem to indicate a tendency to lower promoter and transcriptional activity in OUD, similar to the described changes in OPRM1 [ 52 , 53 ]. In our BPD study, the sites examined by the authors showed no methylation alterations. OPRK1 The methylation analysis of OPRK1 in BPD has recently been described in detail by our group [ 34 ]. Here, focusing on the effects on gene regulation, the identified DMR was found to be located precisely at the 5’ end of the unmethylated CGI around the TSS, with OPRK1-CG144 being in the 3’ end of the CGI. Both sites were hypomethylated in BPD, thus enhancing the shape of the unmethylated domain, the demethylation of which is a prerequisite for transcription factor binding and transcription initiation [ 64 ]. OPRK1-CG17 was highly hypomethylated in BPD. It is located upstream of the promoter at an enhancer and CCCTC-binding factor (CTCF) binding site (ENSR00001280395, ENSR00000855246), and its hypomethylation could promote enhancer binding [ 66 , 67 ]. OPRK1-CG156, located more distally in the first intron, was hypermethylated, its position most likely exerting stabilizing effects on transcription [ 65 ]. Similarly, as has been described in the context of OUD [ 49 ], the results of a study involving 30 heroin and 30 methamphetamine addicts found the average methylation of a promoter fragment of OPRK1 to be increased in drug addicts [ 68 ]. The shared propensity for increased promoter methylation of OR genes in substance abuse suggests a different etiology of methylation changes in substance abuse than in personality disorder, likely representing a consequence rather than a cause of the disorder. OPRL1 The first part of OPRL1 , the NOP gene, that we examined covers approximately 5.5 kb upstream of exon 1 and contains two extensive CGIs, each of which contains several enhancer-binding regions and a promoter region. The most upstream OPRL1-CG8 was hypomethylated in BPD and is located near the 5’ end of the unmethylated CGI including enhancer-binding sequences and the promoter region. More significantly, we found three CG sites (OPRL1-CG155/-CG156/-CG165) to be hypomethylated in BPD, residing at the end of the first CGI downstream of the TSS, the position of which is crucial for influencing transcription [ 50 ]. This effect is amplified by their location in enhancer regions (EH38E2130024-25) [ 66 , 77 ]. Located nearby, downstream, at the beginning of the second CGI and directly 5’ of an enhancer region, OPRL1- CG186 was also hypomethylated. Similarly, we found three more CG sites hypomethylated in BPD (OPRL1-CG308/-CG319/-CG331) at the end of the second CGI that mainly contains enhancer regions and ends with a promoter sequence. Taken together, these seven CG sites hypomethylated in BPD could facilitate transcription initiation and possibly also enhancer binding at the described location. The second part of the OPRL1 gene that we analyzed includes an extended exon 2 promoter-like region (ENSR00001236311) starting midway in intron 1 and extending into intron 3, with only a short hypomethylated region which includes splice regions at the 5’ ends of exon 2 and exon 3. Nearly upstream of the first splice region, within an enhancer sequence (EH38E2130039, ENSR20_C8CPB) that extends beyond the second splice region, we found OPRL1-CG406 being hypermethylated in BPD, thereby possibly impairing enhancer binding [ 66 , 67 ]. Further, if high methylation can provide protective effects against transcriptional interference [ 69 ], we hypothesize that hypermethylation of CG406 in BPD may also protect against alternative splicing [ 70 ]. In short, exon methylation enables RNA polymerase II to rapidly elongate transcripts. CTCF binding leads to the slowing down of the elongation rate, thus enabling the transcriptional inclusion of alternative exons into the transcript. DNA methylation inhibits CTCF binding, leading to increased exon exclusion [ 71 , 72 ]. Thus, the increased methylation rate seen in BPD could promote regular transcription and elongation rates, although we did not analyze transcript variant rates in this study. In contrast, downstream of the translation start site (TLS) in exon 3, within a CTCF-bound distal enhancer (EH38E2130042), we found two adjacent CG sites (OPRL1-CG462/-CG463) being hypomethylated in BPD, thus enabling enhancer and CTCF binding [ 66 , 67 ]. Since distal enhancers can interact with their promoters, building enhancer-promoter loups mediated by CTCF, and can also provide direct local stimulation of transcription elongation as transcription factor recruitment units [ 73 , 74 ], our data indicate a likely enhanced gene transcription activity. Intriguingly, we found a differently methylated region in intron 3, consistent in three adjacent CGs in intron 3, that were notably hypomethylated in BPD (OPRL1-CG508//-CG509/-CG511). Closely upstream, OPRL1-CG502 is hypermethylated in BPD. However, to our knowledge, the functional relevance of this region is not reported. In summary, our findings suggest an increased transcription of OPRL1 in BPD. Several studies have shown a functional antagonism between the stress-promoting CRF and the anti-stress nociceptin/orphanin FQ (N/OFQ) systems [ 75 – 77 ], suggesting an upregulation of NOP in response to stress as a compensatory mechanism in the brain to counteract CRF/stress. This was supported experimentally in a PET study showing increased NOP availability following hydrocortisone administration [ 78 ]. The hypomethylation of OPRL1 that we found in BPD could indicate a similar pathology and, interestingly, also a link to the etiologically significant factor of childhood trauma in BPD. A possible dynamic direction of changes due to trauma-related stress was also suggested by a PET study that revealed increased in vivo binding to midbrain and cerebellum NOPs in women with more severe PTSD symptom score after sexual violence [ 79 ]. Differential methylation in OPRM1 , OPRD1 , OPRK1 , and OPRL1 points to the pathophysiology of core BPD symptoms Viewed collectively, our findings from the individual genes suggest that the methylation changes identified in BPD may lead to altered transcription of the genes OPRM1 , OPRD1 , OPRK1 , and OPRL1 . This reflects the tight interaction and mutual modulation of the OR’s activity [ 44 ]. To our knowledge, the only study on epigenetic changes in OR genes in BPD demonstrated hypomethylation in OPRK1 [ 34 ]. KOR tonically decreases MOR-mediated reward processing, and mediates stress-induced dysphoria, anhedonia and depressive-like behavior [ 32 , 44 , 80 ]. Increased transcription, as suggested by our results, may explain chronical negative affectivity in BPS. In contrast, we found conflicting results of methylation changes in OPRM1 , possibly leading to increased or decreased transcription in BPD. Besides anesthesia, acute activation of MOR mediates reward processing, euphoric and antidepressant-like effects [ 44 ]. Tonical stimulation is responsible for social motivation, the hedonic aspects of social reward, touch, attention, and affection [ 81 – 83 ], aspects that are disrupted in individuals with a history of childhood neglect. In an in vivo PET study using the selective radiotracer [11C]carfentanil, BPD subjects showed an upregulation of the central MORs in relation to an increased activation following experimental provocation of negative affectivity. This suggests hypersensitization of the MOR system, which may explain insensitivity to pain and emotional numbness during severe stress [ 19 ]. A reduced OPRM1 methylation was also found in early life stress [ 57 ], which aligns closely to the etiology of BPS. The inconclusive results of our study in OPRM1 may still point to an unbalanced OR activity. Considering our findings in OPRD1 with a likely stabilized transcription of DOR, KOR and DOR may be seen to partly dominate MOR activity. The partly inhibitory DOR, which regulates MOR effects, tempers mood, mediates motor impulsivity and anesthesia, thus possibly accounts for impulsivity and mood dysregulation in BPD [ 44 ]. In addition to transmitting antihyperalgesic, antiallodynic and antinociceptive effects, NOP also mediates depressant effects by inhibiting noradrenaline and serotonin release [ 77 , 84 , 85 ]. The promoter hypomethylation of OPRL1 in BPD, which suggests an increased transcription of NOP, may therefore explain hypesthesia, the tendency to “freeze,” and depression-like symptoms in BPD subjects as a response to stress. Taken together, the results of our study support the hypothesis of a hypersensitive and dysregulated EOS in BPD, as all analyzed OR genes were found to be epigenetically altered, likely leading to a shift in their mutual interaction and basal excitability. In addition to the findings that suggest low serum levels of endogenous opioids as ligands in subjects with NSSI [ 14 – 16 ], we hypothesize that the ORs in BPD may oscillate between basal under- and stress-induced hyperstimulation. It is this instability between contrary states (high affectivity and the sense of emptiness, hyperarousal and dissociation, and hypo- and hypersensitivity to pain) that represents the core characteristic of BPD symptoms. Insight into this alternating activity therefore enhances the theory of a dysregulated EOS in BPD, which, as a static model, is limited and controversial [ 18 , 86 ]. As the ORs exert multiple controls directly over the brain’s monoaminergic systems [ 44 , 84 ], their impact on motivational and affective symptoms may account for inconsistent or unspecific study results [ 18 ]. Consequently, we sought to analyze if methylation modifications of the ORs occur systematically. By means of correlation analyses, we demonstrated that the methylation rates of certain CG sites of different genes were associated with each other, thus forming an intergenic methylation pattern (Fig. 2 ). However, a significant portion of CG’s methylation did not correlate significantly in our analysis, indicating that each can be independently relevant in association with BPD. For instance, we found few associations between methylation rates in OPRM1 and those of other OR genes. The study highlights the intergenic involvement of epigenetic adaptation processes and the impact of analyses involving entire transmitter systems. That we did not analyze mRNA expression in relation to the altered gene methylation in BPD accounts for a key limitation of our study. However, the influence of methylation on the transcription of the genes we investigated had already been described [ 45 – 49 ]. Further, the study did not analyze the influence of gene variants on gene methylation. In summary, we shed new light on the EOS theory by demonstrating that the methylation of all OR genes is altered in BPD. Thus, a modified gene expression likely explains the pathology of the clinical symptoms in BPD, facilitating a deeper understanding of the biological basis of the interpersonal difficulties and dysfunctional strategies. These findings may encourage the use of new therapeutic strategies, such as opioid antagonists, which modulate EOS sensitivity. In light of this, differential methylation patterns, as identified in our study, can be seen as an individual’s biological risk profile for the development of BPD symptoms. 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Receptor endocytosis counteracts the development of opioid tolerance. Mol Pharmacol 2005; 67(1): 280–287. Finn AK, Whistler JL. Endocytosis of the mu opioid receptor reduces tolerance and a cellular hallmark of opiate withdrawal. Neuron 2001; 32(5): 829–839. Dang VC, Christie MJ. Mechanisms of rapid opioid receptor desensitization, resensitization and tolerance in brain neurons. Br J Pharmacol 2012; 165(6): 1704–1716. Alvarez VA, Arttamangkul S, Dang V, Salem A, Whistler JL, von Zastrow M et al. mu-Opioid receptors: Ligand-dependent activation of potassium conductance, desensitization, and internalization. J Neurosci 2002; 22(13): 5769–5776. Moore LD, Le T, Fan G. DNA methylation and its basic function. Neuropsychopharmacology 2013; 38(1): 23–38. Suzuki MM, Bird A. DNA methylation landscapes: provocative insights from epigenomics. Nat Rev Genet 2008; 9(6): 465–476. Schmidl C, Klug M, Boeld TJ, Andreesen R, Hoffmann P, Edinger M et al. Lineage-specific DNA methylation in T cells correlates with histone methylation and enhancer activity. Genome Res 2009; 19(7): 1165–1174. Jones PA. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet 2012; 13(7): 484–492. Ji H, Liu G, Xu X, Liu H, Xu L, Hu H et al. Hypermethylation of the kappa1 opioid receptor promoter in Chinese heroin and methamphetamine addicts. Exp Ther Med 2018; 16(3): 2392–2398. Bird AP. Gene number, noise reduction and biological complexity. Trends Genet 1995; 11(3): 94–100. Kolathur KK. Role of promoters in regulating alternative splicing. Gene 2021; 782: 145523. Shukla S, Kavak E, Gregory M, Imashimizu M, Shutinoski B, Kashlev M et al. CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing. Nature 2011; 479(7371): 74–79. Lev Maor G, Yearim A, Ast G. The alternative role of DNA methylation in splicing regulation. Trends Genet 2015; 31(5): 274–280. Stadhouders R, van den Heuvel A, Kolovos P, Jorna R, Leslie K, Grosveld F et al. Transcription regulation by distal enhancers: who's in the loop? Transcription 2012; 3(4): 181–186. Ray-Jones H, Spivakov M. Transcriptional enhancers and their communication with gene promoters. Cell Mol Life Sci 2021; 78(19–20): 6453–6485. Ciccocioppo R, de Guglielmo G, Hansson AC, Ubaldi M, Kallupi M, Cruz MT et al. Restraint stress alters nociceptin/orphanin FQ and CRF systems in the rat central amygdala: significance for anxiety-like behaviors. J Neurosci 2014; 34(2): 363–372. Griebel G, Perrault G, Sanger DJ. Orphanin FQ, a novel neuropeptide with anti-stress-like activity. Brain Res 1999; 836(1–2): 221–224. Holanda VAD, Pacifico S, Azevedo Neto J, Finetti L, Lobao-Soares B, Calo G et al. Modulation of the NOP receptor signaling affects resilience to acute stress. J Psychopharmacol 2019; 33(12): 1540–1549. Flanigan M, Tollefson S, Himes ML, Jordan R, Roach K, Stoughton C et al. Acute Elevations in Cortisol Increase the In Vivo Binding of [(11)C]NOP-1A to Nociceptin Receptors: A Novel Imaging Paradigm to Study the Interaction Between Stress- and Antistress-Regulating Neuropeptides. Biol Psychiatry 2020; 87(6): 570–576. Narendran R, Tollefson S, Fasenmyer K, Paris J, Himes ML, Lopresti B et al. Decreased Nociceptin Receptors Are Related to Resilience and Recovery in College Women Who Have Experienced Sexual Violence: Therapeutic Implications for Posttraumatic Stress Disorder. Biol Psychiatry 2019; 85(12): 1056–1064. Knoll AT, Carlezon WA, Jr. Dynorphin, stress, and depression. Brain Res 2010; 1314: 56–73. Chelnokova O, Laeng B, Eikemo M, Riegels J, Loseth G, Maurud H et al. Rewards of beauty: the opioid system mediates social motivation in humans. Mol Psychiatry 2014; 19(7): 746–747. Buchel C, Miedl S, Sprenger C. Hedonic processing in humans is mediated by an opioidergic mechanism in a mesocorticolimbic system. Elife 2018; 7. Meier IM, van Honk J, Bos PA, Terburg D. A mu-opioid feedback model of human social behavior. Neurosci Biobehav Rev 2021; 121: 250–258. Calò G, Lambert DG, Guerrini R. Nociceptin/Orphanin FQ. In: Kastin AJ (ed). Handbook of Biologically Active Peptides , Second Edition edn. Academic Press 2013, pp 1577–1585. Ubaldi M, Cannella N, Borruto AM, Petrella M, Micioni Di Bonaventura MV, Soverchia L et al. Role of Nociceptin/Orphanin FQ-NOP Receptor System in the Regulation of Stress-Related Disorders. Int J Mol Sci 2021; 22(23). Hooley JM, Franklin JC. Why Do People Hurt Themselves? A New Conceptual Model of Nonsuicidal Self-Injury. Clinical Psychological Science 2017; 6(3): 428–451. 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2","display":"","copyAsset":false,"role":"figure","size":169964,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"Figure1MP2.png","url":"https://assets-eu.researchsquare.com/files/rs-7489711/v1/75cc2a1847a2623b8f0c66a6.png"},{"id":97366756,"identity":"fe109d40-e657-4f6b-91ae-44606d7f18fa","added_by":"auto","created_at":"2025-12-03 16:07:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1926156,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7489711/v1/1fbdfc44-69fe-4300-a58d-50cb790ebf7a.pdf"}],"financialInterests":"The authors have declared there is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose","formattedTitle":"The significance of the EOS in borderline personality disorder: epigenetic alterations in OPRM1, OPRD1, OPRK1, and OPRL1","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eAffecting between 0.7 and 2.7% of the general adult population [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], borderline personality disorder (BPD), is one of the most challenging mental conditions. Over the past few decades there has been a significant amount of research on the subject, focusing on the diagnostic classification of BPD, its etiology and neurobiological underpinnings, course, and the efficacy and sustainability of existing treatment strategies [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIt has been hypothesized that brain and personality development is influenced by the interaction of genetic factors and stressful experiences in childhood [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. A recent genome-wide association study on BPD, the largest of its kind, has identified 11 significant genomic loci and nine risk genes, and a high genetic overlap with other mental disorders, especially PTSD, depressive disorder and ADHD [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Environmental factors such as early childhood adversity, including emotional and physical neglect or abuse and sexual violence, are assumed to modulate gene expression, but epigenetic studies on BPD have so far yielded limited and inconsistent results [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eDysfunctions of several neurobiological systems, including serotoninergic, dopaminergic, and other neurotransmitter systems such as oxytocin and the hypothalamic-pituitary-adrenal (HPA) axis [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], have been discussed in the context of neuroendocrine alterations. There is growing evidence that imbalances in the endogenous opioid system (EOS), which is closely linked to the stress system, partly constitute the BPD pathophysiology [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAs a complex neuro-modulatory system, the EOS includes the endogenous opioid neuropeptides beta-endorphins (BE), enkephalins (ENK), dynorphins (DYN), and nociceptin/orphanin FQ (N/OFQ), which act with varying affinity on four groups of receptors: mu (MOR), delta (DOR), kappa (KOR), and nociceptin (NOP) opioid receptors. Together, they play a major role in stress responses, pain modulation, mood and motor regulation, reward processes, and control many other physiological aspects such as respiration, and gastrointestinal, endocrine and immunological functions [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAccording to the \u0026ldquo;EOS theory of BPD\u0026rdquo;, inadequate availability of endogenous opioids, or the altered sensitivity of opioid receptors (OR), leads to functional dysregulation. Negative affectivity, feelings of emptiness and disconnection/loneliness, particularly in stressful situations, may thus be a result of an opioid deficiency leading to dysfunctional behavior such as self-harm, risk-taking behavior, overeating, and drug use aiming to upregulate and restore sufficient EOS activity [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn support of this theory, studies have found reduced BE in CSF and plasma levels in individuals with non-suicidal self-injury (NSSI) [\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], and individual increase of BE saliva levels immediately after NSSI [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. On the other hand, Kao and colleagues\u0026rsquo; longitudinal treatment study involving adolescents did not find significant associations of BE plasma levels with NSSI or BPD-symptoms but with depression [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. A PET study using [(11)C]carfentanil for in vivo quantification of MOR availability provided further evidence by showing elevated baseline receptor concentrations in the amygdala and the nucleus accumbens in female BPD patients, along with increased excitability of the EOS in response to a negative affective stimulus [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. According to the authors of this study, the increased receptor expression was an adaptation to insufficient basal opioid activity. Similarly, Bresin and Gorden discussed the pathophysiology of NSSI as a triad of low basal endogenous opioids, their release through NSSI, and the affect-regulating effect of their release [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTo date, very few studies on endogenous opioid deficiency have covered the full range of BPS symptoms, focusing instead on aspects such as NSSI or depression independent of BPD. With disparate study designs, they have yielded somewhat inconsistent results. For example, pain sensitivity, which is also modulated by BE, has not been found to be associated with basal BE levels in individuals with NSSI [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eFurther indications of the impact of the EOS on BPD symptomatology emerge from treatment studies with opioid antagonists, which have been shown to reduce BPD-associated symptoms [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] such as NSSI [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], binge eating [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], suicidality [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] and dissociation [25.26].\u003c/p\u003e\u003cp\u003eBy inordinately activating the HPA axis early in life, childhood trauma, which is closely related to the development of BPD [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], can lead to genome-wide epigenetic modification of gene transcription, particularly in the gene systems including NR3C1, CRF, AVP [\u003cspan additionalcitationids=\"CR30\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. The HPA axis is closely linked to the EOS with CRF and dynorphin being co-released in stress and both leading to HPA activation involving all ORs [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Recently, we have found a differentially methylated region in the KOR gene (\u003cem\u003eORK1)\u003c/em\u003e that was hypomethylated in BPD and associated with physical and emotional neglect in childhood [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. In line with this, the expression of KOR and DYN has been found to be increased in subjects with NSSI [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn light of this confluence and the findings mentioned above, our study is the first to analyze epigenetic signatures in BPD within the full range of the endogenous opioid receptor (OR) system and evaluate the core sensitivity of the EOS. Based on our hypothesis that BPD subjects exhibit methylation alterations in all OR genes, which may interact with one another, we studied the methylation rates of functionally relevant parts of the OR genes (\u003cem\u003eOPRM1\u003c/em\u003e, \u003cem\u003eOPRD1\u003c/em\u003e, \u003cem\u003eOPRK1\u003c/em\u003e and \u003cem\u003eOPRL1\u003c/em\u003e) in a well-characterized cohort of 47 unmedicated females with BPD and compared them with 48 healthy age-matched female controls.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eSamples\u003c/h2\u003e\u003cp\u003eBiosamples were derived from subjects who took part in different studies within the DFG-funded Clinical Research Unit 256 (KFO256 [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]) and who were recruited between 2012 and 2014 at the Central Institute of Mental Health Mannheim, Germany. The relevant studies were approved by the appropriate Ethics Committee. All participants provided written informed consent including epigenetic analyses.\u003c/p\u003e\u003cp\u003eIn this case-control study, we selected 47 medication-free, non-smoking female patients with a current diagnosis of BPD (\u003cem\u003eM\u003c/em\u003e\u003csub\u003e\u003cem\u003eage\u003c/em\u003e\u003c/sub\u003e=25.21 years, \u003cem\u003eSD\u003c/em\u003e\u003csub\u003e\u003cem\u003eage\u003c/em\u003e\u003c/sub\u003e=4.21; \u003cem\u003eM\u003c/em\u003e\u003csub\u003e\u003cem\u003eBMI\u003c/em\u003e\u003c/sub\u003e=24.28 kg/m\u003csup\u003e2\u003c/sup\u003e, \u003cem\u003eSD\u003c/em\u003e\u003csub\u003e\u003cem\u003eBMI\u003c/em\u003e\u003c/sub\u003e=5.58) and 48 female, non-smoking healthy subjects (\u003cem\u003eM\u003c/em\u003e\u003csub\u003e\u003cem\u003eage\u003c/em\u003e\u003c/sub\u003e=24.71 years, \u003cem\u003eSD\u003c/em\u003e\u003csub\u003e\u003cem\u003eage\u003c/em\u003e\u003c/sub\u003e=3.96; \u003cem\u003eM\u003c/em\u003e\u003csub\u003e\u003cem\u003eBMI\u003c/em\u003e\u003c/sub\u003e=22.88 kg/m\u003csup\u003e2\u003c/sup\u003e, \u003cem\u003eSD\u003c/em\u003e\u003csub\u003e\u003cem\u003eBM\u003c/em\u003e\u003c/sub\u003e=3.79). The general exclusion criteria comprised neurological disorders, current alcohol or drug abuse or dependence in the last 12 months, lifetime diagnosis of schizophrenia, schizoaffective or bipolar disorder, severe medical illness, including cardiac dysregulations, and use of psychotropic medication.\u003c/p\u003e\u003cp\u003eThe diagnostic of BPD was confirmed by means of the International Personality Disorder Examination (IPDE [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]) and the Structured Clinical Interview for the DSM-IV (SCID [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]) was used for the assessment of the exclusion criteria. Childhood adverse experience was measured using the Childhood Trauma Questionnaire (CTQ [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]).\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eDNA methylation analysis\u003c/h3\u003e\n\u003cp\u003eThe analyses were performed on isolated genomic DNA from whole blood samples of each subject. DNA was sheared into fragments of 150\u0026ndash;200 bp by focused-ultrasonic fragmentation using the Covaris S220 sonication system (Covaris Ltd, Brighton, GB). DNA methylation was analyzed via multiplex bisulfide PCR sequencing in accordance with the manufacturer\u0026rsquo;s instructions without modification (SureSelect\u003csup\u003eXT\u003c/sup\u003e Methyl-Seq Target Enrichment System for Illumina Multiplexed Sequencing, Agilent Technologies Inc., Santa Clara, CA, USA).\u003c/p\u003e\u003cp\u003eSequencing was done on an Illumina MiSeq\u003csup\u003e\u0026trade;\u003c/sup\u003e System (2 x 150-bp paired-end) (Illumina Inc., San Diego, CA, USA) followed by demultiplexing and quality control for the generated reads (Q30\u0026thinsp;\u0026gt;\u0026thinsp;90%).\u003c/p\u003e\n\u003ch3\u003eTarget regions of investigated genes\u003c/h3\u003e\n\u003cp\u003eFor the designing of target regions in the investigated genes, localization of exons, translation start site (TLS), promoter and known gene regulation elements were identified using UCSC (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://genome.ucsc.edu\u003c/span\u003e\u003cspan address=\"https://genome.ucsc.edu\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) and ensembl genome browser (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ensembl.org\u003c/span\u003e\u003cspan address=\"https://www.ensembl.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) databases. All gene localizations in this article refer to hg38.\u003c/p\u003e\u003cp\u003eWe analyzed selected regions of the genes \u003cem\u003eOPRM1\u003c/em\u003e (chr6:154034307\u0026ndash;154044307 (10 kb); 100 CG), \u003cem\u003eOPDR1\u003c/em\u003e (chr1:28,807141-28817141 (10 kb), and chr1:28852953\u0026ndash;28862953 (10 kb); 495 CG), \u003cem\u003eOPRL1\u003c/em\u003e (chr20:64074617\u0026ndash;64085617 (11 kb), and chr20:64087687\u0026ndash;64097687 (10 kb); 638 CG). In the analysis of intergenic correlations within the EOS, we included recently published methylation rates of \u003cem\u003eOPRK1\u003c/em\u003e [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], enabling us to analyze the interaction of the complete receptor system. These specified regions constituted part of a customized panel (SureSelect\u003csup\u003eXT\u003c/sup\u003e targeted methyl panel, Agilent Technologies, Inc., CA, USA).\u003c/p\u003e\n\u003ch3\u003eBioinformatics\u003c/h3\u003e\n\u003cp\u003eThe generated fastq files were quality-checked by means of fastqc v0.11.9 [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Adaptors were trimmed using TrimGalore v0.6.7 [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e] and subsequently analyzed with Bismark v0.23.1 [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e] using the embl hg38 primary assembly DNA (GenBank Assembly ID GCA_000001405.28) for reference genome to extract the number of converted and unconverted cytosine for each CG in the targeted genomic region. Statistical analyses were programed and carried out with R (version 4.5.1; R Core Team, 2025). All cytosines of CG\u0026rsquo;s with less than 25 reads or less than 10 remaining samples per group were excluded from calculations.\u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eWe assessed single CG sites\u0026rsquo; methylation rates for the entire sequenced gene regions of \u003cem\u003eOPRM1\u003c/em\u003e, \u003cem\u003eOPRD1\u003c/em\u003e, and \u003cem\u003eOPRL1\u003c/em\u003e. To account for different read counts of individual CG\u0026rsquo;s, we performed logistic regression for all analyses, controlling age and BMI, which resulted in 83 (\u003cem\u003eOPRM1\u003c/em\u003e), 353 (\u003cem\u003eOPRD1\u003c/em\u003e), and 517 (\u003cem\u003eOPRL1\u003c/em\u003e) individual CG sites with enough data. The significance test was performed with the t-value of the difference in log-odds between BPD and HC. To control multiple comparisons, we set the significance level at p .05 with an FDR correction for multiple testing [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eBased on the results of this analysis, we assessed the methylation rate consistency of these in differently methylated CG sites by calculating correlations across participants, controlling for age and BMI. Here we included existing own methylation data of \u003cem\u003eOPRK1\u003c/em\u003e, which originate from the same subjects and the same methylation analysis, and were calculated equally [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. We first investigated correlations within a gene and then between the genes studied using Pearsons\u0026rsquo;s correlation coefficients.\u003c/p\u003e\u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eMethylation rates of 22 distinct CG sites within the targeted regions of\u003c/span\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eOPRM1\u003c/span\u003e, \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eOPRD1\u003c/span\u003e, \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eand OPRL1\u003c/span\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eare different in BPD\u003c/span\u003e\u003c/p\u003e\u003cp\u003eWithin the total of 83 analyzed CG sites across the \u003cem\u003eOPRM1\u003c/em\u003e gene, we found 3 CG sites to be methylated significantly differently between BPD and HC. OPRM1-CG16 was less methylated in BPD, and OPRM1-CG52 and -CG62 were hypermethylated in BPD. As the most upstream site, CG16 is located directly 5\u0026rsquo; before the promoter, whereas OPRM1-CG52 and OPRM1-CG62 are located within exon 1 and intron 1.\u003c/p\u003e\u003cp\u003eAs regards the \u003cem\u003eOPRD1\u003c/em\u003e gene, we found 4 CG sites within the total of 453 analyzed CG sites to be differently methylated between BPD and HC. OPRD1-CG150 is located within intron 1 and was hypermethylated in BPD, the other three significantly differently methylated CG (OPRD1-CG324/-CG331/-CG332) are located within intron 2 close to the 5\u0026rsquo; end of exon 3.\u003c/p\u003e\u003cp\u003eIn the analyzed regions of \u003cem\u003eOPRL1\u003c/em\u003e, we found 15 CG sites being differently methylated in BPD. Apart from OPRL1-CG8, which is in the 5\u0026rsquo;region of the gene, OPRL1-CG155, -CG156, -CG165, -CG186, -CG308, -CG319, and -CG331 are located in the intron 1. There, they are situated inside functional regions such as enhancer sequences (OPRL1-CG155/-CG156/-CG165), the second promoter (OPRL1-CG308/-CG319/-CG331). All of these were less methylated in BPD. Further differentially methylated CG sites were OPRL1-CG406, located at the end of intron 1 (230 bp upstream of exon 2), which was hypermethylated in BPD, and six CG sites in intron 3: OPRL1-CG462 and -CG463, less methylated in BPD, located consecutively, OPRL1-CG502, hypermethylated in BPD, and -CG508, -CG509, and -CG511, all less methylated in BPD, located closely to one another and before exon 4.\u003c/p\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e summarize the results and locations within the genes.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eMethylation rates of individual CG sites within \u003cem\u003eOPRM1\u003c/em\u003e, \u003cem\u003eOPRD1\u003c/em\u003e, \u003cem\u003eOPRK1\u003c/em\u003e, and \u003cem\u003eOPRL1\u003c/em\u003e that differ significantly between subjects with BPD and HC, significance level at p .05 with an FDR-correction for multiple testing (Benjamini and Hochberg). *CG related to E3 start, **CG related to TLS, \u003csup\u003e#\u003c/sup\u003eGescher et al. [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"11\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCG-ID\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCG related to TLS\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eposition related to TLS\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003egene \u003c/p\u003e\u003cp\u003eregion\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003echr\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eposition \u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eBPD methylation rate [%]\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHC methylation rate [%]\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eOdds-\u003c/p\u003e\u003cp\u003eRatio\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003et-value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value (adjusted)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOPRM1-CG16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e-23\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-488\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e154039058\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e26.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e29.74\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.171\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e5.279\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOPRM1-CG52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e14\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e206\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eE1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e154039751\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e17.38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e15.91\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.866\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e-3.288\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.039\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOPRM1-CG62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e24\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e429\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e154039974\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e43.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e40.33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.896\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e-3.192\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.039\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOPRD1-CG150\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e86\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1805\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e28814189\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e92.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e90.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.759\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e-4.150\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.004\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOPRD1-CG324\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e-15*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e49735\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e28862119\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e57.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e65.83\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.509\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e5.103\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOPRD1-CG331\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e-8*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e50071\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e28862455\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e76.48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e78.79\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.126\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e3.537\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.036\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOPRD1-CG332\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e-7*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e50082\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e28862466\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e86.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e89.12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.244\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e4.986\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOPRK1-CG17\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e-106\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-3478\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eupstream\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e53254514\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e81.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e81.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.898\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e10.186\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOPRK1-CG34\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e-89\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-1162\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eupstream\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e53252198\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e33.36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e36.32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.134\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e3.560\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.016\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOPRK1-CG35\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e-88\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-1116\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eupstream\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e53252152\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e54.86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e55.99\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.098\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e3.118\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.038\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOPRK1-CG36\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e-87\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-1101\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eupstream\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e53252137\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e60.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e62.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.118\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e3.189\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.034\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOPRK1-CG37\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e-86\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-993\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eupstream\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e53252029\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e66.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e68.67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.101\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e3.721\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.016\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOPRK1-CG38\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e-85\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-978\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eupstream\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e53252014\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e53.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e55.23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.092\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e3.191\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.034\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOPRK1-CG144\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e41\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e512\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e53250525\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e54.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e56.57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.102\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e3.564\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.016\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOPRK1-CG156\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e53\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2508\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e53248529\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e91.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e94.98\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.874\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e-3.347\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.027\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOPRL1-CG8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e-182**\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-17451\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5' region\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e64075271\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e90.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e92.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.211\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e3.669\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.014\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOPRL1-CG155\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e38**\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-12114\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e64080608\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e24.67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e26.60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.108\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e3.234\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.042\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOPRL1-CG156\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e39**\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-12110\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e64080612\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e29.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e31.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.119\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e3.720\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.014\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOPRL1-CG165\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e48**\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-11772\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e64080950\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e33.78\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e36.80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.140\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e3.584\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.018\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOPRL1-CG186\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e69**\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-10597\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e64082125\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e23.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e26.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.173\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e4.878\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOPRL1-CG308\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e230**\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-8132\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e64084590\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e34.58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e36.93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.110\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e3.291\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.039\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOPRL1-CG319\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e245**\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-7773\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e64084949\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e16.22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e20.21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.309\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e3.275\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.039\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOPRL1-CG331\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e257**\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-7629\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e64085093\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e58.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e62.07\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.153\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e3.663\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.014\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOPRL1-CG406\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e-36\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-972\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e64091750\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e86.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e84.87\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.857\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e-3.979\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.006\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOPRL1-CG462\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e21\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e625\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e64093346\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e67.48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e76.92\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.513\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e10.276\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOPRL1-CG463\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e22\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e630\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e64093351\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e80.60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e83.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.176\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e3.436\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.028\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOPRL1-CG502\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e64\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3427\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e64096148\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e86.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e84.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.869\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e-3.376\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.032\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOPRL1-CG508\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e70\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3842\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e64096563\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e52.61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e54.31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.191\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e6.998\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOPRL1-CG509\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e71\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3906\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e64096627\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e87.83\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e91.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.636\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e9.871\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOPRL1-CG511\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e73\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3967\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e64096688\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e88.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e92.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.646\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e7.091\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eCorrelation analyses of differentially methylated CG sites in\u003c/span\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eOPRM1\u003c/span\u003e, \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eOPRD1\u003c/span\u003e, \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eOPRK1, and OPRL1\u003c/span\u003e\u003c/p\u003e\n\u003ch3\u003eSignificant intragenic correlations between CG sites methylated differently in BPD\u003c/h3\u003e\n\u003cp\u003eWe found no correlations for \u003cem\u003eOPRM1\u003c/em\u003e within the investigated CG sites, which were significantly altered in BPD. Within the four differentially methylated CG sites in \u003cem\u003eOPRD1\u003c/em\u003e, we found only OPRD1-CG331 and -CG332 to be highly positively correlated with each other (r\u0026thinsp;=\u0026thinsp;.6663, p\u0026thinsp;\u003cem\u003e\u0026lt;\u0026thinsp;.0001\u003c/em\u003e). The methylation rate in \u003cem\u003eOPRK1\u003c/em\u003e showed a positive correlation at the adjacent sites OPRK1-CG36/-CG37/-CG38, and -CG144, and, except for -CG37, also with -CG35. In \u003cem\u003eOPRL1\u003c/em\u003e, OPRL1-CG156, -CG165, -CG186, -CG308, -CG329 and -CG331 were positively correlated with one another, and negatively with CG502, thus forming a cluster of similarly and oppositely deviating methylation in BPD. We summarized all statistical indicators of the significant intergenic correlations in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCorrelation between methylation rates of CG sites in \u003cem\u003eOPRM1\u003c/em\u003e, \u003cem\u003eOPRD1, OPRK1\u003c/em\u003e, and \u003cem\u003eOPRL1\u003c/em\u003e that are differentially methylated in BPD vs. HC, controlled for age and BMI (Pearson's correlation coefficients). Only significant correlations are depicted.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"31\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c15\" colnum=\"15\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c16\" colnum=\"16\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c17\" colnum=\"17\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c18\" colnum=\"18\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c19\" colnum=\"19\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c20\" colnum=\"20\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c21\" colnum=\"21\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c22\" colnum=\"22\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c23\" colnum=\"23\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c24\" colnum=\"24\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c25\" colnum=\"25\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c26\" colnum=\"26\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c27\" colnum=\"27\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c28\" colnum=\"28\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c29\" colnum=\"29\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c30\" colnum=\"30\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c31\" colnum=\"31\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003er (\u003cem\u003ep\u003c/em\u003e)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOPRM1-CG16\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOPRM1-CG52\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eOPRM1-CG62\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eOPRD1-CG150\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eOPRD1-CG324\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eOPRD1-CG331\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eOPRD1-CG332\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eOPRK1-CG17\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" 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colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c16\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c18\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c19\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c20\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c21\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c22\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c23\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c24\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c25\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c26\"\u003e\u003cp\u003e1\u003c/p\u003e\u003cp\u003e\u003cem\u003e(N/A)\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c27\"\u003e\u003cp\u003e\u003cb\u003e0.431\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e(\u0026lt;\u0026thinsp;0.001)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c28\"\u003e\u003cp\u003e-0.135\u003c/p\u003e\u003cp\u003e\u003cem\u003e(0.2)\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c29\"\u003e\u003cp\u003e\u003cb\u003e-0.535\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e(\u0026lt;\u0026thinsp;0.001)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c30\"\u003e\u003cp\u003e-0.137\u003c/p\u003e\u003cp\u003e\u003cem\u003e(0.192)\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c31\"\u003e\u003cp\u003e-0.152\u003c/p\u003e\u003cp\u003e\u003cem\u003e(0.147)\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eOPRL1-CG463\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c16\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c18\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c19\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c20\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c21\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c22\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c23\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c24\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c25\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c26\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c27\"\u003e\u003cp\u003e1\u003c/p\u003e\u003cp\u003e\u003cem\u003e(N/A)\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c28\"\u003e\u003cp\u003e-0.037\u003c/p\u003e\u003cp\u003e\u003cem\u003e(0.726)\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c29\"\u003e\u003cp\u003e\u003cb\u003e-0.274\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e(0.008)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c30\"\u003e\u003cp\u003e0.105\u003c/p\u003e\u003cp\u003e\u003cem\u003e(0.32)\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c31\"\u003e\u003cp\u003e0.092\u003c/p\u003e\u003cp\u003e\u003cem\u003e(0.381)\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eOPRL1-CG502\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c16\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c18\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c19\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c20\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c21\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c22\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c23\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c24\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c25\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c26\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c27\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c28\"\u003e\u003cp\u003e1\u003c/p\u003e\u003cp\u003e\u003cem\u003e(N/A)\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c29\"\u003e\u003cp\u003e\u003cb\u003e0.265\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e(0.010)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c30\"\u003e\u003cp\u003e0.020\u003c/p\u003e\u003cp\u003e\u003cem\u003e(0.848)\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c31\"\u003e\u003cp\u003e0.031\u003c/p\u003e\u003cp\u003e\u003cem\u003e(0.767)\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eOPRL1-CG508\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c16\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c18\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c19\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c20\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c21\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c22\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c23\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c24\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c25\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c26\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c27\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c28\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c29\"\u003e\u003cp\u003e1\u003c/p\u003e\u003cp\u003e\u003cem\u003e(N/A)\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c30\"\u003e\u003cp\u003e\u003cb\u003e-0.289\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e(0.005)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c31\"\u003e\u003cp\u003e\u003cb\u003e-0.274\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e(0.008)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eOPRL1-CG509\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c16\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c18\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c19\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c20\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c21\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c22\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c23\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c24\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c25\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c26\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c27\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c28\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c29\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c30\"\u003e\u003cp\u003e1\u003c/p\u003e\u003cp\u003e\u003cem\u003e(N/A)\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c31\"\u003e\u003cp\u003e\u003cb\u003e0.991\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e(\u0026lt;\u0026thinsp;0.001)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eOPRL1-CG511\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c16\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c18\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c19\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c20\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c21\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c22\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c23\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c24\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c25\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c26\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c27\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c28\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c29\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c30\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c31\"\u003e\u003cp\u003e1\u003c/p\u003e\u003cp\u003e\u003cem\u003e(N/A)\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"31\"\u003eR Pearson's correlation coefficient, \u003cem\u003ep p\u003c/em\u003e-value.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\n\u003ch3\u003eSignificant intergenic correlations of CG sites methylated differently in BPD\u003c/h3\u003e\n\u003cp\u003eConsidering all the investigated gene regions, we found individual CG sites of different genes whose methylation rates were correlated. We identified such intergenic correlations between almost all genes, except between \u003cem\u003eOPRM1\u003c/em\u003e and \u003cem\u003eOPRD1\u003c/em\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eFor example, the methylation rates of two CG sites of both the \u003cem\u003eOPRM1\u003c/em\u003e and the \u003cem\u003eOPRK1\u003c/em\u003e genes were correlated with each other (OPRM1-CG52 with OPRK1-CG17 and OPRM1-CG62 with OPRK1-CG36). Further significant intergenic correlations for \u003cem\u003eOPRM1\u003c/em\u003e were found with CG sites of \u003cem\u003eOPRL1\u003c/em\u003e (OPRM1-CG16 and -CG62 each with OPRL1-CG509 and -CG511), but with none in \u003cem\u003eOPRD1\u003c/em\u003e.\u003c/p\u003e\u003cp\u003eIn \u003cem\u003eOPRD1\u003c/em\u003e, the methylation rates of OPRD1-CG331 and -CG33, which had a strong positive correlation with each other, correlated positively with 3 CG sites in \u003cem\u003eOPRL1\u003c/em\u003e (OPRL1-CG8/-CG463/-CG502). Also, the methylation rate of OPRD1-CG331 correlated negatively with those of OPRL1-CG155 and -CG156.\u003c/p\u003e\u003cp\u003eIn addition to the ones described for \u003cem\u003eOPRM1\u003c/em\u003e, the methylation of specific CGs of \u003cem\u003eOPRK1\u003c/em\u003e correlated with selected CGs in \u003cem\u003eOPRL1\u003c/em\u003e and \u003cem\u003eOPRD1\u003c/em\u003e. Notably, the methylation rate of OPRK1-CG37 correlated positively with those of six CGs in \u003cem\u003eOPRL1\u003c/em\u003e (OPRL1-CG8/-CG155/-CG156/-CG165/-CG308/-CG319), five of which are part of the intragenic cluster identified in \u003cem\u003eOPRL1.\u003c/em\u003e This results in an extended intergenic methylation cluster that also omits any correlations with \u003cem\u003eOPRM1\u003c/em\u003e.\u003c/p\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e summarizes all statistical indicators of the significant intergenic correlations.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this study, we sought to provide an integrative view of methylation changes in the entire set of OR in BPD as they are all involved in the mediation of stress response [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] and mutual regulation [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. We found methylation alterations in all the genes examined (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Their individual significance with respect to gene activity, including that of \u003cem\u003eOPRK1\u003c/em\u003e, is discussed below [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. The epigenetic control of OR by promoter methylation has been repeatedly demonstrated [\u003cspan additionalcitationids=\"CR46 CR47 CR48\" citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. Moreover, we found associations between the methylation rates of the CG sites altered in BPD at the \u003cem\u003eOPRM1\u003c/em\u003e, \u003cem\u003eOPRD1\u003c/em\u003e, \u003cem\u003eOPRK1\u003c/em\u003e, and \u003cem\u003eOPRL1\u003c/em\u003e genes, identifying epigenetic interactions or joint activities within the transmitter systems. The results are discussed with respect to a possible link with the core clinical symptoms of BPD.\u003c/p\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eOPRM1\u003c/h2\u003e\u003cp\u003eOur results revealed a highly significant hypomethylation in BPD subjects at the 5\u0026rsquo; end of the promoter unmethylated domain of \u003cem\u003eOPRM1\u003c/em\u003e (CG16), and hypermethylation of two CG sites downstream at the end of exon 1 (OPRM1-CG52) and the 5\u0026rsquo; end of intron 1 (OPRM1-CG62), both located shortly downstream of the promoter region, which is already known to be epigenetically regulated [\u003cspan additionalcitationids=\"CR46\" citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. The hypermethylation of CG52 and CG62 in BPD may be more relevant as the methylation downstream of the TSS including the first exon is more crucial for transcription [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. The impact of CG52 hypermethylation is further enhanced by its location in an enhancer region, which can interfere with enhancer binding. Conversely, only CG16 is in the promoter region, but is significantly hypomethylated in BPD. Taken together, our results are contradictory and limit a functional analysis of their transcriptional impact.\u003c/p\u003e\u003cp\u003eTo our knowledge, there is no other epigenetic study on \u003cem\u003eOPRM1\u003c/em\u003e and BPD. Previous studies found a region within the first exon including parts of the promoter region being hypermethylated in patients with alcohol dependence [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. Hypermethylation of distinct CGs in this region was also found in patients with opioid dependence or chronic use and could most likely be the result of the drug [\u003cspan additionalcitationids=\"CR53 CR54\" citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e]. This assumption is supported by studies that found newborns of mothers who used morphine during pregnancy to exhibit hypermethylation within the \u003cem\u003eOPRM1\u003c/em\u003e promoter and increased withdrawal symptoms after birth [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eInterestingly, a significant hypomethylation of 11 consecutive CGs within the \u003cem\u003eOPRM1\u003c/em\u003e promoter region was found in extremely preterm infants in response to and in correlation with neonatal stress exposure [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]. These findings differ from those obtained in studies on early substance exposure [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e, \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e]. Stress, for example, evokes the release of various transmitters including endogenous opioids, with complex effects on the neural network. They are rapidly metabolized to enable a highly flexible excitatory system. This means that brain amino peptides such as enkephalins are immediately hydrolyzed after release and are degraded by endopeptidases, resulting in the very short half-life of endogenous peptides [\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e]. The effect of endogenous opioids on MOR is further limited due to their rapid endocytosis and recycling in the cell through strong coupling of intracellular mechanisms, which prevents tolerance [\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e]. Morphine, by contrast, fails to induce receptor endocytosis by binding to MOR, and the resensitization of MOR is impaired, which leads to the aberrantly prolonged signaling that in turn contributes to cellular morphine tolerance [\u003cspan additionalcitationids=\"CR62\" citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAlong with the much longer half-life compared to those of endogenous opioids, the different ways in which morphine and several other opioid drugs [\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e] work on MORs, including causing adaptive intracellular changes, can help explain why epigenetic changes in opioid use [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e, \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e] are different from those linked to early life stress [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]. The effects of neonatal stress exposure [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e] with hypomethylation of parts of the \u003cem\u003eOPRM1\u003c/em\u003e promoter are most similar to our findings in BPD, which also align with early stress experiences in the BPD etiology.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eOPRD1\u003c/h2\u003e\u003cp\u003eIn the sequences of the DOR gene \u003cem\u003eOPRD1\u003c/em\u003e that we analyzed, we found four CG sites that were differently methylated in BPD. Unlike \u003cem\u003eOPRM1\u003c/em\u003e, we found no methylation alterations in the promoter, exon 1, and an enhancer binding site (EH38E1332550), which are most likely functionally relevant for transcription initiation [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. As the most proximal differently methylated CG site, OPRD1-CG150, located in intron 1, was hypermethylated in BPD. Its hypermethylation could contribute to transcriptional stability, since high DNA methylation within the gene body is associated with a higher level of gene expression and transcriptional elongation, and is supposed to protect against interference with the transcription process [\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e, \u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e]. The other CG sites differently methylated in BPD were found close to one another, immediately 5\u0026rsquo; to exon 3, and were all less highly methylated in BPD (OPRD1-CG324/-CG331/-CG332). Nearby, upstream of these, was a distal enhancer binding sequence involved in the control of gene expression (ENSR00000352119). How this interacts with the transcription start site (TSS) or directly modulates the transcription of exon 3 has not been specified in detail. We hypothesize that hypomethylation in this region, as identified in our study, may facilitate the binding of enhancers or other transcription factors. Taken together, our data suggest an increased transcription stability of the gene \u003cem\u003eOPRD1\u003c/em\u003e in BPD.\u003c/p\u003e\u003cp\u003eIn their study analyzing 12, 25, and 45 CpG sites in the promoter regions of the \u003cem\u003eOPRM1\u003c/em\u003e, \u003cem\u003eOPRD\u003c/em\u003e, and \u003cem\u003eOPRK1\u003c/em\u003e genes, Yu et al. found several individual CG sites of \u003cem\u003eOPRD1\u003c/em\u003e and \u003cem\u003eOPRK1\u003c/em\u003e that were more highly methylated in subjects with opioid use disorder (OUD), but not after Bonferroni correction [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. Their nominal results seem to indicate a tendency to lower promoter and transcriptional activity in OUD, similar to the described changes in \u003cem\u003eOPRM1\u003c/em\u003e [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. In our BPD study, the sites examined by the authors showed no methylation alterations.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eOPRK1\u003c/h2\u003e\u003cp\u003eThe methylation analysis of \u003cem\u003eOPRK1\u003c/em\u003e in BPD has recently been described in detail by our group [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Here, focusing on the effects on gene regulation, the identified DMR was found to be located precisely at the 5\u0026rsquo; end of the unmethylated CGI around the TSS, with OPRK1-CG144 being in the 3\u0026rsquo; end of the CGI. Both sites were hypomethylated in BPD, thus enhancing the shape of the unmethylated domain, the demethylation of which is a prerequisite for transcription factor binding and transcription initiation [\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e]. OPRK1-CG17 was highly hypomethylated in BPD. It is located upstream of the promoter at an enhancer and CCCTC-binding factor (CTCF) binding site (ENSR00001280395, ENSR00000855246), and its hypomethylation could promote enhancer binding [\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e, \u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e]. OPRK1-CG156, located more distally in the first intron, was hypermethylated, its position most likely exerting stabilizing effects on transcription [\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eSimilarly, as has been described in the context of OUD [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e], the results of a study involving 30 heroin and 30 methamphetamine addicts found the average methylation of a promoter fragment of \u003cem\u003eOPRK1\u003c/em\u003e to be increased in drug addicts [\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e]. The shared propensity for increased promoter methylation of OR genes in substance abuse suggests a different etiology of methylation changes in substance abuse than in personality disorder, likely representing a consequence rather than a cause of the disorder.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eOPRL1\u003c/h2\u003e\u003cp\u003eThe first part of \u003cem\u003eOPRL1\u003c/em\u003e, the NOP gene, that we examined covers approximately 5.5 kb upstream of exon 1 and contains two extensive CGIs, each of which contains several enhancer-binding regions and a promoter region. The most upstream OPRL1-CG8 was hypomethylated in BPD and is located near the 5\u0026rsquo; end of the unmethylated CGI including enhancer-binding sequences and the promoter region. More significantly, we found three CG sites (OPRL1-CG155/-CG156/-CG165) to be hypomethylated in BPD, residing at the end of the first CGI downstream of the TSS, the position of which is crucial for influencing transcription [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. This effect is amplified by their location in enhancer regions (EH38E2130024-25) [\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e, \u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e]. Located nearby, downstream, at the beginning of the second CGI and directly 5\u0026rsquo; of an enhancer region, OPRL1- CG186 was also hypomethylated. Similarly, we found three more CG sites hypomethylated in BPD (OPRL1-CG308/-CG319/-CG331) at the end of the second CGI that mainly contains enhancer regions and ends with a promoter sequence. Taken together, these seven CG sites hypomethylated in BPD could facilitate transcription initiation and possibly also enhancer binding at the described location.\u003c/p\u003e\u003cp\u003eThe second part of the \u003cem\u003eOPRL1\u003c/em\u003e gene that we analyzed includes an extended exon 2 promoter-like region (ENSR00001236311) starting midway in intron 1 and extending into intron 3, with only a short hypomethylated region which includes splice regions at the 5\u0026rsquo; ends of exon 2 and exon 3. Nearly upstream of the first splice region, within an enhancer sequence (EH38E2130039, ENSR20_C8CPB) that extends beyond the second splice region, we found OPRL1-CG406 being hypermethylated in BPD, thereby possibly impairing enhancer binding [\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e, \u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e]. Further, if high methylation can provide protective effects against transcriptional interference [\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e], we hypothesize that hypermethylation of CG406 in BPD may also protect against alternative splicing [\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e]. In short, exon methylation enables RNA polymerase II to rapidly elongate transcripts. CTCF binding leads to the slowing down of the elongation rate, thus enabling the transcriptional inclusion of alternative exons into the transcript. DNA methylation inhibits CTCF binding, leading to increased exon exclusion [\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e, \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e]. Thus, the increased methylation rate seen in BPD could promote regular transcription and elongation rates, although we did not analyze transcript variant rates in this study.\u003c/p\u003e\u003cp\u003eIn contrast, downstream of the translation start site (TLS) in exon 3, within a CTCF-bound distal enhancer (EH38E2130042), we found two adjacent CG sites (OPRL1-CG462/-CG463) being hypomethylated in BPD, thus enabling enhancer and CTCF binding [\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e, \u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e]. Since distal enhancers can interact with their promoters, building enhancer-promoter loups mediated by CTCF, and can also provide direct local stimulation of transcription elongation as transcription factor recruitment units [\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e, \u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e], our data indicate a likely enhanced gene transcription activity.\u003c/p\u003e\u003cp\u003eIntriguingly, we found a differently methylated region in intron 3, consistent in three adjacent CGs in intron 3, that were notably hypomethylated in BPD (OPRL1-CG508//-CG509/-CG511). Closely upstream, OPRL1-CG502 is hypermethylated in BPD. However, to our knowledge, the functional relevance of this region is not reported.\u003c/p\u003e\u003cp\u003eIn summary, our findings suggest an increased transcription of \u003cem\u003eOPRL1\u003c/em\u003e in BPD. Several studies have shown a functional antagonism between the stress-promoting CRF and the anti-stress nociceptin/orphanin FQ (N/OFQ) systems [\u003cspan additionalcitationids=\"CR76\" citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e], suggesting an upregulation of NOP in response to stress as a compensatory mechanism in the brain to counteract CRF/stress. This was supported experimentally in a PET study showing increased NOP availability following hydrocortisone administration [\u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e]. The hypomethylation of \u003cem\u003eOPRL1\u003c/em\u003e that we found in BPD could indicate a similar pathology and, interestingly, also a link to the etiologically significant factor of childhood trauma in BPD. A possible dynamic direction of changes due to trauma-related stress was also suggested by a PET study that revealed increased in vivo binding to midbrain and cerebellum NOPs in women with more severe PTSD symptom score after sexual violence [\u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eDifferential methylation in\u003c/span\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eOPRM1\u003c/span\u003e, \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eOPRD1\u003c/span\u003e, \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eOPRK1\u003c/span\u003e, \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eand\u003c/span\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eOPRL1\u003c/span\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003epoints to the pathophysiology of core BPD symptoms\u003c/span\u003e\u003c/p\u003e\u003cp\u003eViewed collectively, our findings from the individual genes suggest that the methylation changes identified in BPD may lead to altered transcription of the genes \u003cem\u003eOPRM1\u003c/em\u003e, \u003cem\u003eOPRD1\u003c/em\u003e, \u003cem\u003eOPRK1\u003c/em\u003e, and \u003cem\u003eOPRL1\u003c/em\u003e. This reflects the tight interaction and mutual modulation of the OR\u0026rsquo;s activity [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTo our knowledge, the only study on epigenetic changes in OR genes in BPD demonstrated hypomethylation in \u003cem\u003eOPRK1\u003c/em\u003e [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. KOR tonically decreases MOR-mediated reward processing, and mediates stress-induced dysphoria, anhedonia and depressive-like behavior [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e]. Increased transcription, as suggested by our results, may explain chronical negative affectivity in BPS. In contrast, we found conflicting results of methylation changes in \u003cem\u003eOPRM1\u003c/em\u003e, possibly leading to increased or decreased transcription in BPD. Besides anesthesia, acute activation of MOR mediates reward processing, euphoric and antidepressant-like effects [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. Tonical stimulation is responsible for social motivation, the hedonic aspects of social reward, touch, attention, and affection [\u003cspan additionalcitationids=\"CR82\" citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e], aspects that are disrupted in individuals with a history of childhood neglect. In an in vivo PET study using the selective radiotracer [11C]carfentanil, BPD subjects showed an upregulation of the central MORs in relation to an increased activation following experimental provocation of negative affectivity. This suggests hypersensitization of the MOR system, which may explain insensitivity to pain and emotional numbness during severe stress [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. A reduced \u003cem\u003eOPRM1\u003c/em\u003e methylation was also found in early life stress [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e], which aligns closely to the etiology of BPS. The inconclusive results of our study in \u003cem\u003eOPRM1\u003c/em\u003e may still point to an unbalanced OR activity. Considering our findings in \u003cem\u003eOPRD1\u003c/em\u003e with a likely stabilized transcription of DOR, KOR and DOR may be seen to partly dominate MOR activity. The partly inhibitory DOR, which regulates MOR effects, tempers mood, mediates motor impulsivity and anesthesia, thus possibly accounts for impulsivity and mood dysregulation in BPD [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn addition to transmitting antihyperalgesic, antiallodynic and antinociceptive effects, NOP also mediates depressant effects by inhibiting noradrenaline and serotonin release [\u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e, \u003cspan citationid=\"CR84\" class=\"CitationRef\"\u003e84\u003c/span\u003e, \u003cspan citationid=\"CR85\" class=\"CitationRef\"\u003e85\u003c/span\u003e]. The promoter hypomethylation of \u003cem\u003eOPRL1\u003c/em\u003e in BPD, which suggests an increased transcription of NOP, may therefore explain hypesthesia, the tendency to \u0026ldquo;freeze,\u0026rdquo; and depression-like symptoms in BPD subjects as a response to stress.\u003c/p\u003e\u003cp\u003eTaken together, the results of our study support the hypothesis of a hypersensitive and dysregulated EOS in BPD, as all analyzed OR genes were found to be epigenetically altered, likely leading to a shift in their mutual interaction and basal excitability.\u003c/p\u003e\u003cp\u003eIn addition to the findings that suggest low serum levels of endogenous opioids as ligands in subjects with NSSI [\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], we hypothesize that the ORs in BPD may oscillate between basal under- and stress-induced hyperstimulation. It is this instability between contrary states (high affectivity and the sense of emptiness, hyperarousal and dissociation, and hypo- and hypersensitivity to pain) that represents the core characteristic of BPD symptoms. Insight into this alternating activity therefore enhances the theory of a dysregulated EOS in BPD, which, as a static model, is limited and controversial [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR86\" class=\"CitationRef\"\u003e86\u003c/span\u003e]. As the ORs exert multiple controls directly over the brain\u0026rsquo;s monoaminergic systems [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR84\" class=\"CitationRef\"\u003e84\u003c/span\u003e], their impact on motivational and affective symptoms may account for inconsistent or unspecific study results [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eConsequently, we sought to analyze if methylation modifications of the ORs occur systematically. By means of correlation analyses, we demonstrated that the methylation rates of certain CG sites of different genes were associated with each other, thus forming an intergenic methylation pattern (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). However, a significant portion of CG\u0026rsquo;s methylation did not correlate significantly in our analysis, indicating that each can be independently relevant in association with BPD. For instance, we found few associations between methylation rates in \u003cem\u003eOPRM1\u003c/em\u003e and those of other OR genes. The study highlights the intergenic involvement of epigenetic adaptation processes and the impact of analyses involving entire transmitter systems.\u003c/p\u003e\u003cp\u003eThat we did not analyze mRNA expression in relation to the altered gene methylation in BPD accounts for a key limitation of our study. However, the influence of methylation on the transcription of the genes we investigated had already been described [\u003cspan additionalcitationids=\"CR46 CR47 CR48\" citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. Further, the study did not analyze the influence of gene variants on gene methylation.\u003c/p\u003e\u003cp\u003eIn summary, we shed new light on the EOS theory by demonstrating that the methylation of all OR genes is altered in BPD. Thus, a modified gene expression likely explains the pathology of the clinical symptoms in BPD, facilitating a deeper understanding of the biological basis of the interpersonal difficulties and dysfunctional strategies. These findings may encourage the use of new therapeutic strategies, such as opioid antagonists, which modulate EOS sensitivity. In light of this, differential methylation patterns, as identified in our study, can be seen as an individual\u0026rsquo;s biological risk profile for the development of BPD symptoms. In future studies, epigenetic risk scores can serve as a correlate for the biological impact and efficacy of therapeutic interventions.\u003c/p\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eCONFLICT OF INTEREST\u003c/h2\u003e\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eACKNOWLEDGMENTS\u003c/h2\u003e\u003cp\u003eThis study was part of the central project of the Clinical Research Unit on Mechanisms of Disturbed Emotion Processing in Borderline Personality Disorder (KFO 256). The research was supported by the German Research Foundation.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eEaton NR, Greene AL. 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A New Conceptual Model of Nonsuicidal Self-Injury. \u003cem\u003eClinical Psychological Science\u003c/em\u003e 2017; 6(3): 428\u0026ndash;451.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"translational-psychiatry","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"tp","sideBox":"Learn more about [Translational Psychiatry](http://www.nature.com/tp/)","snPcode":"41398","submissionUrl":"https://mts-tp.nature.com/cgi-bin/main.plex","title":"Translational Psychiatry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7489711/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7489711/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe high relevance of childhood trauma in the etiology of borderline personality disorder (BPD) is likely due to epigenetic adaptations associated with exhaustive stress early in life. There is increasing evidence that imbalances in the endogenous opioid system (EOS), which is tightly linked to the stress system, underlie part of the BPD pathophysiology.\u003c/p\u003e\u003cp\u003eThe aim of this study was to first investigate DNA methylation differences in the promoter regions of the opioid receptor (OR) genes \u003cem\u003eOPRM1\u003c/em\u003e, \u003cem\u003eOPRD1\u003c/em\u003e, and \u003cem\u003eOPRL1\u003c/em\u003e in subjects with BPD (N\u0026thinsp;=\u0026thinsp;47) and in healthy controls (N\u0026thinsp;=\u0026thinsp;48). Analyzing individual CG nucleotides (N\u0026thinsp;=\u0026thinsp;1233), we identified differentially methylated CG sites in \u003cem\u003eOPRM1\u003c/em\u003e (N\u0026thinsp;=\u0026thinsp;3), \u003cem\u003eOPRD1\u003c/em\u003e (N\u0026thinsp;=\u0026thinsp;4), and \u003cem\u003eOPRL1\u003c/em\u003e (N\u0026thinsp;=\u0026thinsp;15). Our findings indicate an increased transcription of these less methylated genes.\u003c/p\u003e\u003cp\u003eFurther, to study the OR system in its entirety, we analyzed the methylation rate correlation of the CG sites identified to have been differentially methylated in \u003cem\u003eOPRM1\u003c/em\u003e, \u003cem\u003eOPRD1\u003c/em\u003e, and \u003cem\u003eOPRL1\u003c/em\u003e, including existing data of \u003cem\u003eOPRK1\u003c/em\u003e. Distinct associations of the methylation rates were found to form intragenic and intergenic methylation clusters, indicating the impact of methylation alterations on the OR system, and the concurrent activation and mutual regulation of ORs.\u003c/p\u003e\u003cp\u003eTogether, our findings suggest altered transcription of all OR genes, which likely leads to EOS hypersensitivity and dysregulation, resulting in an unbalanced hyperactivation of inhibitory and disinhibitory effects that may account for the core BPD symptoms. In addition, the observed BPD-related methylation changes in OR genes and their partial synchronization support the role of the EOS in BPD pathobiology.\u003c/p\u003e","manuscriptTitle":"The significance of the EOS in borderline personality disorder: epigenetic alterations in OPRM1, OPRD1, OPRK1, and OPRL1","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-01 11:17:23","doi":"10.21203/rs.3.rs-7489711/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"translational-psychiatry","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"tp","sideBox":"Learn more about [Translational Psychiatry](http://www.nature.com/tp/)","snPcode":"41398","submissionUrl":"https://mts-tp.nature.com/cgi-bin/main.plex","title":"Translational Psychiatry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4c46f548-4645-4346-80ff-f7d2ee351243","owner":[],"postedDate":"December 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":54351638,"name":"Biological sciences/Genetics"},{"id":54351639,"name":"Biological sciences/Molecular biology"},{"id":54351640,"name":"Health sciences/Diseases/Psychiatric disorders"}],"tags":[],"updatedAt":"2025-12-01T11:17:23+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-01 11:17:23","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7489711","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7489711","identity":"rs-7489711","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}