New-born females show higher stress- and genotype-independent methylation of SLC6A4 than males.

Helene Dukal,Manfred Laucht,Josef Frank,Moshe Szyf,Maren Lang,Jens Treutlein,Bertram Krumm,Maria Gilles,Michael Deuschle,Renaud Massart,Marcella Rietschel,Isabell Ac Wolf,Stephanie H Witt

doi:10.1186/s40479-015-0029-6

Abstract

BackgroundResearch has demonstrated an association between exposure to early life stress and an increased risk of psychiatric disorders in later life, in particular depression. However, the mechanism through which early life stress contributes to disease development remains unclear. Previous studies have reported an association between early life stress and altered methylation of the serotonin transporter gene (SLC6A4), a key candidate gene for several psychiatric disorders. These differences in methylation are influenced by sex and genetic variation in the SLC6A4-linked polymorphic region (5-HTTLPR). Furthermore, one study indicated that stress during pregnancy may induce methylation changes in SLC6A4 in the newborn. The present study is the first to investigate whether early life stress during pregnancy impacts on SLC6A4 methylation in newborns, taking into account the influence of genetic variation and sex.MethodsCord blood was obtained from newborns with high (n = 45) or low (n = 45) early life stress, defined as maternal stress during pregnancy. The effect on methylation of early life stress, 5-HTTLPR genotype, and sex was assessed at four cytosin-phosphate-guanine dinucleotide (CpG) sites in the promoter associated CpG island north shore (CpG 1 to 4). The epigenetic analyses focused on these CpG sites, since research has shown that CpG island shore methylation has functional consequences.ResultsSignificant sex-specific methylation was observed, with females displaying higher methylation levels than males (p < 0.001). Importantly, this effect was influenced by neither early life stress nor genotype.ConclusionsThe present data suggest that sex-specific methylation of SLC6A4 is present at birth, and is independent of early life stress and 5-HTTLPR genotype. This may contribute to the sex-specific prevalence of depression.Electronic supplementary materialThe online version of this article (doi:10.1186/s40479-015-0029-6) contains supplementary material, which is available to authorized users.

Highlights

Research has demonstrated an association between exposure to early life stress and an increased risk of psychiatric disorders in later life, in particular depression
This 5-HTTLPR consists of a 44-base-pair insertion/deletion polymorphism in the 5′ regulatory promoter region of SLC6A4, which results in a short (S) and long (L) allele of the gene and a single nucleotide polymorphism in the L allele of 5-HTTLPR which leads to a triallelic locus (S/LA/LG) [3]
The aims of the present study were to determine 1) whether exposure to maternal stress during pregnancy leads to higher methylation levels in SLC6A4 in newborns; and 2) whether this is influenced by sex and 5-HTTLPR genotype

Summary

Introduction

Research has demonstrated an association between exposure to early life stress and an increased risk of psychiatric disorders in later life, in particular depression. Previous studies have reported an association between early life stress and altered methylation of the serotonin transporter gene (SLC6A4), a key candidate gene for several psychiatric disorders. These differences in methylation are influenced by sex and genetic variation in the SLC6A4linked polymorphic region (5-HTTLPR). The present study is the first to investigate whether early life stress during pregnancy impacts on SLC6A4 methylation in newborns, taking into account the influence of genetic variation and sex. Research has shown that variation in this gene is associated with stress-related psychiatric disorders, such as major depression and anxiety [2].

Objectives

Methods

Results

Discussion

Conclusion