Cancer & Disease Epigenetics, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC, Australia.
INSERM, Univ Montpellier, Neuropsychiatry: Epidemiological and Clinical Research, Montpellier, France.
BMC Psychiatry. 2018 Sep 4;18(1):282. doi: 10.1186/s12888-018-1850-4.
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. 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.
The 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).
Nominally 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).
We 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.
血清素能信号传递中断通常是抑郁症的一个特征，负责血清素再摄取的血清素转运体基因 (SLC6A4) 在这方面受到了广泛关注。大多数研究都集中在多态性 5-HTTLPR 上游重复序列或启动子 CpG 岛的 DNA 甲基化上。很少有研究探索基因内遗传变异对 DNA 甲基化的影响，以及它们与抑郁风险的综合关联。本研究旨在确定 SLC6A4 基因内的遗传变异是否影响启动子 DNA 甲基化，以及这些变异是否与抑郁状态相关。
ESPRIT 研究涉及一个基于社区的老年人群体（>65 岁）。根据 DSM-IV（美国精神病学协会，1994 年）标准诊断出重度抑郁症（MDD），并通过流行病学研究抑郁量表（CES-D）评估严重抑郁症状。使用 Sequenom MassARRAY 测量 SLC6A4 甲基化状态（n=302）。
SLC6A4 遗传变异（5-HTTLPR、rs140700、rs4251417、rs6354、rs25528、rs25531）与几个 CpG 位点的 DNA 甲基化之间存在名义上的显著关联。在多元回归中，DNA 甲基化与抑郁状态相关，但仅在存在特定基因型时才相关。在短 5-HTTLPR 和 5-HTTLPR/r25531 等位基因纯合的个体中，两个 CpG 位点的低甲基化与抑郁相关（β=−0.44 至β=−0.31；p=0.001 至 p=0.038）。
我们提供了证据表明 SLC6A4 甲基化与抑郁之间存在基因型依赖性关联。遗传变异也可能在影响启动子甲基化水平及其与抑郁的关联方面发挥作用。
