Epigenetics-by-sex interaction for somatization conferred by methylation at the promoter region of SLC6A4 gene.

BACKGROUND: Depression, anxiety and somatoform disorders are all more prevalent in women than in men. However, specific biological mechanisms contributing to such sex differences remain unknown. Serotonergic pathways are involved in mood and behavior regulation and thus have been suggested to be altered in several psychiatric disorders. The serotonin transporter (SERT), encoded by SLC6A4 gene, has received major attention due to its crucial role in serotonergic transmission. METHODS: 148 monozygotic twin subjects were assessed for (i) lifetime categorical diagnosis of anxious-depressive disorders, following SCID-I-based DSM-IV criteria, and (ii) current psychiatric symptomatology, from a dimensional approach, by means of the Brief Symptom Inventory (BSI). SLC6A4 gene methylation was analyzed by means of Infinium HumanMethylation450 in a subset of the sample. CpG-specific methylation at the promoter region of SLC6A4 gene was further analyzed by means of pyrosequencing technology in the total sample. RESULTS: SLC6A4 methylation was found to be significantly higher in women when compared to men independent of DSM-IV diagnosis. SLC6A4 methylation was further associated with the BSI-derived somatization dimension. CONCLUSIONS: Female hypermethylation of a discrete region located within SLC6A4 promoter region could underlie differential SERT expression in women when compared to men and could be one of the causative mechanisms by which women exhibit increased prevalence of somatic symptoms.

An integrative review of methylation at the serotonin transporter gene and its dialogue with environmental risk factors, psychopathology and 5-HTTLPR.

Gene-environment (G×E) interactions have largely been regarded as the root of many complex disorders, including several psychiatric disorders. In this regard, it has been hypothesized that epigenetic mechanisms may be the main mediators of such interactions. Of particular interest is the previously described interaction between psychosocial stress and genetic variability of the serotonin transporter gene (SLC6A4) in its polymorphic region 5-HTTLPR. Here we review the literature concerning SLC6A4 methylation in association with environmental, clinical or genetic variables. While SLC6A4 hypermethylation has typically been described to be independently associated with both early life stress and depressive disorders, only a few papers address whether methylation could mediate the interaction between stress and 5-HTTLPR in predicting psychopathological risk. Nevertheless, research preliminarily indicates a methylation-driven increased vulnerability of carriers of the short allele of 5-HTTLPR to psychiatric disorders when exposed to early stress or soon after exposure to stress.

Maternal psychosocial stress during pregnancy alters the epigenetic signature of the glucocorticoid receptor gene promoter in their offspring: a meta-analysis.

Prenatal stress has been widely associated with a number of short- and long-term pathological outcomes. Epigenetic mechanisms are thought to partially mediate these environmental insults into the fetal physiology. One of the main targets of developmental programming is the hypothalamic-pituitary-adrenal (HPA) axis as it is the main regulator of the stress response. Accordingly, an increasing number of researchers have recently focused on the putative association between DNA methylation at the glucocorticoid receptor gene (NR3C1) and prenatal stress, among other types of psychosocial stress. The current study aims to systematically review and meta-analyze the existing evidence linking several forms of prenatal stress with DNA methylation at the region 1F of the NR3C1 gene. The inclusion of relevant articles allowed combining empirical evidence from 977 individuals by meta-analytic techniques, whose methylation assessments showed overlap across 5 consecutive CpG sites (GRCh37/hg19 chr5:142,783,607-142,783,639). From this information, methylation levels at CpG site 36 displayed a significant correlation to prenatal stress (r = 0.14, 95% CI: 0.05-0.23, P = 0.002). This result supports the proposed association between a specific CpG site located at the NR3C1 promoter and prenatal stress. Several confounders, such as gender, methylation at other glucocorticoid-related genes, and adjustment for pharmacological treatments during pregnancy, should be taken into account in further studies.

Further evidence of DEPDC7 DNA hypomethylation in depression: A study in adult twins.

Late and early stressful factors have widely been recognized to play a role in the aetiology of depression. Recent research indicates that such adverse environmental stimuli may alter gene expression in humans via epigenetic modifications. While epigenetic changes such as DNA methylation are likely involved in these processes, it is still unknown what specific genomic loci may be hyper- or hypo-methylated in depression. The association between depressive symptoms during the last 30 days (Brief Symptom Inventory [BSI]) and peripheral-blood DNA methylation levels at genomic loci previously reported as epigenetically altered in saliva and brain of depressive patients was evaluated in a community sample of 34 adult Caucasian MZ twins (17 pairs). Intrapair DNA methylation differences in an intron of DEPDC7 (chr11:33040743) were associated with intrapair differences in current depressive symptoms. Accordingly, a site-specific 10% DNA hypomethylation in a co-twin would correlate with a current depressive symptom score around 3.1 BSI points above the score of his/her less-depressed co-twin. These findings indicate that DEPDC7 hypomethylation in peripheral blood DNA may be associated with recent depressive symptomatology, in line with previous results.