Methylation of the SLC6a2 Gene Promoter in Major Depression and Panic Disorder

Richard Bayles,Assam El-Osta,David Barton,Emma K Baker,Jeremy B M Jowett,Murray Esler,Gavin Lambert,Jorg Tost

doi:10.1371/journal.pone.0083223

Richard Bayles, Assam El-Osta + Show 6 more

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https://doi.org/10.1371/journal.pone.0083223

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Abstract

Reduced function of the noradrenaline transporter (NET) has been demonstrated in patients with major depressive disorder (MDD) and panic disorder. Attempts to explain NET dysfunction in MDD and panic disorder by genetic variation in the NET gene SLC6a2 have been inconclusive. Transcriptional silencing of the SLC6a2 gene may be an alternative mechanism which can lead to NET dysfunction independent of DNA sequence. The objective of this study was to characterise the DNA methylation state of the SLC6a2 gene promoter in patients with MDD and panic disorder. SLC6a2 promoter methylation was also analysed before and after antidepressant treatment. This study was performed with DNA from blood, using bisulphite sequencing and EpiTYPER methylation analyses. Patients with MDD or panic disorder were not found to differ significantly from healthy controls in the pattern of methylation of the SLC6a2 gene promotor. While significant correlations between methylation levels at some CpG sites and physiological measures were identified, overall the variation in DNA methylation between patients was small, and the significance of this variation remains equivocal. No significant changes in SLC6a2 promoter methylation were observed in response to antidepressant treatment. Further in-depth analysis of alternative mechanisms of transcriptional regulation of the SLC6a2 gene in human health and disease would be of value.

Highlights

Reduced noradrenaline transporter (NET) function has been demonstrated in patients with major depressive disorder (MDD), and panic disorder [1,2]
Anxiety scores were higher in patients with MDD and panic disorder, and heart rate was higher in panic disorder patients (Table 2)
Methylation of the SLC6a2 gene promoter The SLC6a2 gene has been hypothesised to be repressed in human diseases where evidence of NET dysfunction exists due to an increase in DNA methylation of the SLC6a2 gene promoter [6,21]

Summary

Introduction

Reduced NET function has been demonstrated in patients with major depressive disorder (MDD), and panic disorder [1,2]. Extensive attempts to explain NET dysfunction in MDD and panic disorder by association with DNA sequence variation in the NET gene SLC6a2 have been inconclusive, yielding weak association results and rare functional sequence variation [3]. The cause of NET dysfunction in these patient groups remains to be elucidated, transcriptional silencing of the SLC6a2 gene has been hypothesised. NET dysfunction in patients with panic disorder [6] Based on these preliminary findings, a hypothesis was formed that with the development of panic disorder, the SLC6a2 promoter is hypermethylated, leading to transcriptional repression of the SLC6a2 gene

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