PDF(Pubmed)
Abstract：
BACKGROUND: 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-HT4) in a cohort of healthy individuals (N = 254) and, for 5-HT4, 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-HT4 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.
RESULTS: 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.
CONCLUSIONS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：5-羟色胺相关基因的甲基化已被认为是一种可能介导环境胁迫的合理基因与环境的联系，抑郁和焦虑症状。DNA甲基化通常在血细胞中测量，但对这种外周表观遗传修饰与脑5-羟色胺能结构之间的关联知之甚少。这里,我们评估了5-羟色胺转运蛋白（SLC6A4）中4个CpG位点的全血甲基化和色氨酸羟化酶2（TPH2）基因的6个CpG位点与5-羟色胺转运蛋白（5-HTT）和5-羟色胺4受体（5-HT4）在一组健康个体（N=254）和，对于5-HT4，在一组未用药的抑郁症患者中（N=90）。要做到这一点，我们使用亚硫酸氢盐焦磷酸测序定量SLC6A4/TPH2甲基化,并使用正电子发射断层扫描估计大脑5-HT4和5-HTT水平.此外,我们探讨了SLC6A4和TPH2甲基化与早期生命和近期压力测量之间的关联，297名健康个体的抑郁和焦虑症状。
结果：我们发现，在抑郁症患者或健康个体中，外周DNA甲基化与5-羟色胺能神经传递的脑标志物之间没有统计学上的显著关联。此外,尽管SLC6A4CpG2（chr17：30,236,083）甲基化与健康队列中的亲本结合库存过度保护评分略微相关，在考虑了血细胞异质性后,没有保持统计学意义.
结论：我们建议在脑5-羟色胺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甲基化作为环境压力的生物标志物的作用。抑郁或焦虑症状。
结果：我们发现，在抑郁症患者或健康个体中，外周DNA甲基化与5-羟色胺能神经传递的脑标志物之间没有统计学上的显著关联。此外,尽管SLC6A4CpG2（chr17：30,236,083）甲基化与健康队列中的亲本结合库存过度保护评分略微相关，在考虑了血细胞异质性后,没有保持统计学意义.
结论：我们建议在脑5-羟色胺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甲基化作为环境压力的生物标志物的作用。抑郁或焦虑症状。
