Association study of polymorphism in the serotonin transporter gene promoter, methylation profiles, and expression in patients with major depressive disorder

Abstract

The serotonin transporter (5HTT) may be associated with the pathogenesis of major depressive disorder (MDD). The 5HTT-linked polymorphic region (5HTTLPR) genotype may determine how levels of 5HTT mRNA are influenced by promoter methylation. We examined the association of 5HTT gene methylation, which influences gene expression, and the 5HTTLPR genotype before antidepressant treatment and expression before and after treatment. The aims of this study were (1) to investigate the association between 5HTT methylation or expression in leukocytes and depression and (2) to investigate a possible effect of 5HTT methylation, expression, and genotype on clinical symptoms in MDD. The 5HTTLPR genotype was significantly associated with mean methylation levels in patients only (patients: r = 0.40, p = 0.035, controls: p = 0.96). The mean methylation level was significantly increased in patients compared with controls (patients: 5.30 ± 0.24, controls: 4.70 ± 0.19, unpaired t-test, p = 0.04). 5HTT expression using real-time PCR and Taqman probes was increased in unmedicated patients compared with controls and then decreased 8 weeks after antidepressant treatment. The mean 5HTT expression level was not associated with the 5HTTLPR genotype in patients or controls. Increased depressive symptoms were related to decreased levels of methylation. Copyright © 2016 John Wiley & Sons, Ltd.

Genotype-dependent associations between serotonin transporter gene (SLC6A4) DNA methylation and late-life depression

“…Several studies support our findings, reporting no association between SLC6A4 methylation in blood and depression in adults, in either Caucasian [12] or three Asian ( n  = 108; n  = 286; n  = 100) [14, 15, 17] populations, as well as in buccal mucosa from Caucasian adolescents ( n  = 150) [16] and EBV-transformed lymphoblasts ( n  = 192) [18]. In contrast, three studies found positive associations between peripheral SLC6A4 methylation in blood and depression in Caucasian ( n  = 57) [13] and Asian adults ( n  = 151; n  = 84) [19, 20], two of which had overlapping assay regions with our study [19, 20]. Interestingly, Shi et al (2016) found significantly highermethylation at two CpG sites (∆ = 2.52 and 0.15) corresponding to CpG 25.26 in our study, which we failed to find, despite this unit having the highest level and variability of methylation.…”

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

“…Similarly, Okada and colleagues found higher SLC6A4 methylation at a specific CpG site to be positively correlated to the improvement ratio; interestingly, methylation at this particular CpG site was inversely correlated to early trauma in the study (Okada et al, 2014). Nevertheless, Kang et al found less Hamilton Depression Rating Scale (HAM-D), Hamilton Anxiety Rating Scale (HAM-A) and Social and Occupational Functional Assessment Scale (SOFAS) improvement to be related to higher methylation ; furthermore, Iga et al reported higher CpG-specific methylation to be associated with less improvement in depressive symptoms as measured by the HAM-D scale (Iga et al, 2016).…”

“…Notably, both Wankerl et al and Iga et al did find an association between CpG-specific methylation and mRNA expression in peripheral blood suggesting that correlations between methylation and expression cannot be obtained from average methylation percentages but can from CpG-specific analysis. Notably, Iga et al found this association in patients but not in controls (Iga et al, 2016).…”

“…Conversely, van Mil et al reported s carriers to exhibit lower SLC6A4 methylation and to be at increased risk of developing ADHD (van Mil et al, 2014); likewise, Iga and colleagues found l carriers to exhibit increased methylation but only in the depressed group (Iga et al, 2016).…”

“…While some authors found clear associations between methylation of different regions of the SLC6A4 promoter and depression (Iga et al, 2016;Lei et al, 2015;Okada et al, 2014;Philibert et al, 2008;Schneider et al, 2015;van der Knaap et al, 2015b), there were also models of indirect effects mediated by brain function (Swartz et al, 2016) and findings that only reached statistical significance when incorporating genotype (5-HTTLPR) into the statistical model Olsson et al, 2010). Notably, using a monozygotic twin sample, Beck Depression Inventory (BDI) scores were found to correlate to SLC6A4 methylation levels in an intrapair differences design, which allows genetic confounding to be avoided (Zhao et al, 2013a).…”