Abstract
BackgroundDisrupted serotonergic signaling is often a feature of depression and the role of the serotonin transporter gene (SLC6A4), responsible for serotonin re-uptake, has received much attention in this regard. Most studies have focused on the polymorphic 5-HTTLPR upstream repeat, or DNA methylation at the promoter CpG island. Few studies have explored the influence of genetic variation across the gene on DNA methylation, and their combined association with depression risk. The aim of this study was to determine whether genetic variation in the SLC6A4 gene influences promoter DNA methylation, and whether these are associated with depression status.MethodThe ESPRIT study involves a community-based population of older individuals (> 65 years of age). Major depressive disorder (MDD) was diagnosed according to DSM-IV (American Psychiatric Association, 1994) criteria, and severe depressive symptoms assessed by the Centre for Epidemiological Studies Depression (CES-D) Scale. Sequenom MassARRAY was used to measure SLC6A4 methylation status (n = 302).ResultsNominally significant associations were observed between SLC6A4 genetic variants (5-HTTLPR, rs140700, rs4251417, rs6354, rs25528, rs25531) and DNA methylation at several CpG sites. In multivariate regression, DNA methylation was associated with depression status, but only in the presence of specific genotypes. In individuals homozygous for the short 5-HTTLPR and 5-HTTLPR/r25531 alleles, lower methylation at two CpGs was associated with depression (β = − 0.44 to β = − 0.31; p = 0.001 to p = 0.038).ConclusionWe present evidence for genotype-dependent associations between SLC6A4 methylation and depression. Genetic variants may also play a role in influencing promoter methylation levels and its association with depression.
Highlights
Disrupted serotonergic signaling is often a feature of depression and the role of the serotonin transporter gene (SLC6A4), responsible for serotonin re-uptake, has received much attention in this regard
Nominally significant associations were observed between SLC6A4 genetic variants (5-HTTLPR, rs140700, rs4251417, rs6354, rs25528, rs25531) and DNA methylation at several CpG sites
Using data gathered as part of a large general population cohort study of older persons, this study firstly investigated whether SLC6A4 genetic variation across the gene influences promoter DNA methylation and secondly, whether depression is associated with DNA methylation independently and/or in combination with genetic variation
Summary
Disrupted serotonergic signaling is often a feature of depression and the role of the serotonin transporter gene (SLC6A4), responsible for serotonin re-uptake, has received much attention in this regard. Few studies have explored the influence of genetic variation across the gene on DNA methylation, and their combined association with depression risk. The aim of this study was to determine whether genetic variation in the SLC6A4 gene influences promoter DNA methylation, and whether these are associated with depression status. Serotonin deficiency was one of the earliest hypothesis of depression causality [1, 2] This came from the discovery of a class of antidepressants, the selective serotonin re-uptake inhibitors (SSRIs), which block the reuptake of the neurotransmitter and increasing its availability. There is some evidence that 5-HTTLPR genotype affects vulnerability to a broad range of behavioural disorders including depression [1] These associations have not been consistently found [7], suggesting that other regulatory mechanisms and factors are likely to contribute to depression risk [8,9,10]
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