Epigenetic genes and emotional reactivity to daily life events: a multi-step gene-environment interaction study

Abstract

Recent human and animal studies suggest that epigenetic mechanisms mediate the impact of environment on development of mental disorders. Therefore, we hypothesized that polymorphisms in epigenetic-regulatory genes impact stress-induced emotional changes. A multi-step, multi-sample gene-environment interaction analysis was conducted to test whether 31 single nucleotide polymorphisms (SNPs) in epigenetic-regulatory genes, i.e. three DNA methyltransferase genes DNMT1, DNMT3A, DNMT3B, and methylenetetrahydrofolate reductase (MTHFR), moderate emotional responses to stressful and pleasant stimuli in daily life as measured by Experience Sampling Methodology (ESM). In the first step, main and interactive effects were tested in a sample of 112 healthy individuals. Significant associations in this discovery sample were then investigated in a population-based sample of 434 individuals for replication. SNPs showing significant effects in both the discovery and replication samples were subsequently tested in three other samples of: (i) 85 unaffected siblings of patients with psychosis, (ii) 110 patients with psychotic disorders, and iii) 126 patients with a history of major depressive disorder. Multilevel linear regression analyses showed no significant association between SNPs and negative affect or positive affect. No SNPs moderated the effect of pleasant stimuli on positive affect. Three SNPs of DNMT3A (rs11683424, rs1465764, rs1465825) and 1 SNP of MTHFR (rs1801131) moderated the effect of stressful events on negative affect. Only rs11683424 of DNMT3A showed consistent directions of effect in the majority of the 5 samples. These data provide the first evidence that emotional responses to daily life stressors may be moderated by genetic variation in the genes involved in the epigenetic machinery.

Figure 1. Results of multilevel regression analyses estimating the association between daily stressful life events and NA, as a function of SNP rs11683424 in the DNMT3A gene.

The buffering effects were consistently observed in individuals carrying the T allele in three samples of (A) healthy control subjects (B) female twins from the general population, and (C) patients with a history of at least one episode of major depressive disorder, currently having residual depressive symptoms.

Figure 2. A schematic overview of two major protein-coding transcripts of the DNMT3A gene.

The numbered blocks are exons, the connecting lines introns. Genetic variability in DNMT3A mainly occurs in intronic regions while the exonic regions are very well conserved. The dashed line indicates the location of the tagSNP rs11683424, which we found to significantly moderate the association between daily stressful events and negative affect. The DNMT3A2 transcript seems to be regulated by an alternative promoter upstream of exon 7, and bears a unique untranslated exon 4 kb upstream of exon 7 (termed exon 7a). rs11683424 is situated upstream of the DNMT3A2 transcription start site. Gene structure and names of the protein coding transcripts were derived from the Ensembl database (www.ensembl.org).