Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Clin Epigenetics. 2024 May 27;16(1):71. doi: 10.1186/s13148-024-01678-y.
Methylation of serotonin-related genes has been proposed as a plausible gene-by-environment link which may mediate environmental stress, depressive and anxiety symptoms. DNA methylation is often measured in blood cells, but little is known about the association between this peripheral epigenetic modification and brain serotonergic architecture. Here, we evaluated the association between whole-blood-derived methylation of four CpG sites in the serotonin transporter (SLC6A4) and six CpG sites of the tryptophan hydroxylase 2 (TPH2) gene and in-vivo brain levels of serotonin transporter (5-HTT) and serotonin 4 receptor (5-HT) in a cohort of healthy individuals (N = 254) and, for 5-HT in a cohort of unmedicated patients with depression (N = 90). To do so, we quantified SLC6A4/TPH2 methylation using bisulfite pyrosequencing and estimated brain 5-HT and 5-HTT levels using positron emission tomography. In addition, we explored the association between SLC6A4 and TPH2 methylation and measures of early life and recent stress, depressive and anxiety symptoms on 297 healthy individuals.
We found no statistically significant association between peripheral DNA methylation and brain markers of serotonergic neurotransmission in patients with depression or in healthy individuals. In addition, although SLC6A4 CpG2 (chr17:30,236,083) methylation was marginally associated with the parental bonding inventory overprotection score in the healthy cohort, statistical significance did not remain after accounting for blood cell heterogeneity.
We suggest that findings on peripheral DNA methylation in the context of brain serotonin-related features should be interpreted with caution. More studies are needed to rule out a role of SLC6A4 and TPH2 methylation as biomarkers for environmental stress, depressive or anxiety symptoms.
血清素相关基因的甲基化被认为是一种合理的基因-环境关联，它可能介导环境压力、抑郁和焦虑症状。DNA 甲基化通常在血细胞中测量，但人们对这种外周表观遗传修饰与大脑血清素能结构之间的关联知之甚少。在这里，我们评估了健康个体（N=254）全血中血清素转运体（SLC6A4）的四个 CpG 位点和色氨酸羟化酶 2（TPH2）基因的六个 CpG 位点以及体内血清素转运体（5-HTT）和 5-羟色胺 4 受体（5-HT）的水平之间的关联，并在未经药物治疗的抑郁症患者（N=90）中对 5-HT 进行了研究。为此，我们使用亚硫酸氢盐焦磷酸测序来量化 SLC6A4/TPH2 甲基化，并使用正电子发射断层扫描来估计大脑 5-HT 和 5-HTT 水平。此外，我们在 297 名健康个体中探索了 SLC6A4 和 TPH2 甲基化与早期生活和近期压力、抑郁和焦虑症状之间的关联。
我们没有发现抑郁症患者或健康个体中外周 DNA 甲基化与血清素能神经传递的大脑标志物之间存在统计学上显著的关联。此外，尽管 SLC6A4 CpG2（chr17:30,236,083）甲基化与健康队列中的父母养育量表过度保护评分呈边缘相关，但在考虑血细胞异质性后，统计学意义不复存在。
我们建议，在大脑与血清素相关特征的背景下，对外周 DNA 甲基化的发现应谨慎解释。需要更多的研究来排除 SLC6A4 和 TPH2 甲基化为环境压力、抑郁或焦虑症状的生物标志物的作用。
