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Aberrant methylation of gene associated CpG sites occurs in borderline personality disorder - PubMed

  • ️Tue Jan 01 2013

Aberrant methylation of gene associated CpG sites occurs in borderline personality disorder

Stefanie Teschler et al. PLoS One. 2013.

Abstract

Borderline personality disorder (BPD) is a complex psychiatric disease with an increased impact in the last years. While the diagnosis and therapy are well established, little is known on the pathogenesis of borderline personality disorder. Previously, a significant increase in DNA methylation of relevant neuropsychiatric genes in BPD patients has been reported. In our study we performed genome wide methylation analysis and revealed specific CpG sites that exhibited increased methylation in 24 female BPD patients compared to 11 female healthy controls. Bead chip technology and quantitative bisulfite pyrosequencing showed a significantly increased methylation at CpG sites of APBA2 (1.1 fold) and APBA3 (1.1 fold), KCNQ1 (1.5 fold), MCF2 (1.1 fold) and NINJ2 (1.2 fold) in BPD patients. For the CpG sites of GATA4 and HLCS an increase in DNA methylation was observed, but was only significant in the bead chip assay. Moreover genome wide methylation levels of blood samples of BPD patients and control samples are similar. In summary, our results show a significant 1.26 fold average increase in methylation at the analyzed gene associated CpG sites in the blood of BPD patients compared to controls samples (p<0.001). This data may provide new insights into epigenetic mechanisms underlying the pathogenesis of BPD.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Methylation rate at 27,578 individual CpG target sites from 24 female BPD patients and 11 female control samples.

Scatter plot of pairwise comparison between female BPD patients and controls (A) and volcano plot for visualization of differentially methylated probes between both groups (B). Methylation levels of 27,578 CpGs sites were revealed by HumanMethylation27 bead chip technology and the average beta-value (beta) and the absolute DiffScore for patients and control groups was determined. Beta is the ratio of the methylated signal to the sum of unmethylated and methylated signal. The DiffScore is a transformation of the p-value that provides directionality to the p-value based on the difference between the average signal in the reference group vs. the comparison group. The formula is: DiffScore = 10*sgn(µcond-µref)*log10p; For a p-value of 0.05 the DiffScore is ~13. 259 CpGs exhibited a significantly higher DiffScore (≥13). Analyzed CpGs of APBA2, APBA3, GATA4, HLCS, KCNQ1, MCF2, NINJ2 and TAAR5 are indicated.

Figure 2
Figure 2. Map of the investigated genomic regions.

Positions of the analyzed CpG sites of APBA2, APBA3, GATA4, HLCS, KCNQ1, MCF2, NINJ2 and TAAR5 are shown (

http://genome.ucsc.edu

). CpGs are indicated with vertical lines and the analyzed CpGs are numbered. The bold and underlined CpG sites were identified as differentially methylated in the 27K bead chip assay. Primers and transcriptions start sites are marked with arrows. Graphics were generated with the python.vs.cobra program (

https://launchpad.net/python.vs.cobra

).

Figure 3
Figure 3. Methylation analysis of APBA2, APBA3, GATA4, HLCS, KCNQ1, MCF2, NINJ2 and TAAR5 by bisulfite pyrosequencing.

PCR products obtained from three independent bisulfite treated DNA of female BPD patients (n=9) and controls (n=8) were analyzed. Average methylation levels ± SD of individual CpG sites from three independent pyrosequencing reactions are indicated and summarized for all CpGs. Significant p-values are indicated (two-tailed t-test).

Figure 4
Figure 4. Methylation changes between female BPD patients and controls.

The quotient between mean methylation levels at individual CpG sites and combined sites for APBA2, APBA3, GATA4, HLCS, KCNQ1, MCF2, NINJ2 and TAAR5 in BPD patients and controls were calculated and plotted. P-values are indicated (two-tailed t-test).

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Grants and funding

Research in Reinhard Dammann’s laboratory is funded by Land Hessen (LOEWE) and Deutsche Forschungsgemeinschaft (TRR81). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.