Objective: Major depressive disorder (MDD) arises from a combination of genetic and environmental risk factors and DNA methylation is one of the molecular mechanisms through which these factors can manifest. However, little is known about the epigenetic signature of MDD in brain tissue. This study aimed to investigate associations between brain tissue-based DNA methylation and late-life MDD. Methods: We performed a brain epigenome-wide association study (EWAS) of late-life MDD in 608 participants from the Religious Order Study and the Rush Memory and Aging Project (ROS/MAP) using DNA methylation profiles of the dorsal lateral prefrontal cortex (dPFC) generated using the Illumina HumanMethylation450 Beadchip array. We also conducted an EWAS of MDD in each sex separately. Results: We found epigenome-wide significant associations between brain-tissue-based DNA methylation and late-life MDD. The most significant and robust association was found with altered methylation levels in the YOD1 locus (cg25594636, p-value=2.55 x 10^-11; cg03899372, p-value=3.12 x 10^-09; cg12796440, p-value=1.51 x 10^-08, cg23982678, p-value=7.94 x 10^-08). Analysis of differentially methylated regions (DMR, p-value=5.06 x 10^-10) further confirmed this locus. Other significant loci include UGT8 (cg18921206, p-value=1.75 x 10^-08), FNDC3B (cg20367479, p-value=4.97 x 10^-08) and SLIT2 (cg10946669, p-value=8.01 x 10^-08). Notably, brain-tissue based methylation levels were strongly associated with late-life MDD in men more than in women. Conclusions: We identified altered methylation in the YOD1, UGT8, FNDC3B and SLIT2 loci as new epigenetic factors associated with late-life MDD. Furthermore, our study highlights the sex-specific molecular heterogeneity of MDD.

中文翻译：

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脑组织中的DNA甲基化水平与社区参与者的晚期抑郁症之间的关联

目的：重度抑郁症（MDD）是由遗传和环境风险因素共同作用而引起的，而DNA甲基化是这些因素可通过其表现出来的分子机制之一。但是，关于脑组织中MDD的表观遗传学特征知之甚少。这项研究旨在调查基于脑组织的DNA甲基化与晚期MDD之间的关联。方法：我们使用背面外侧前额叶皮层的DNA甲基化图谱，对来自宗教秩序研究和仓促记忆与衰老项目（ROS / MAP）的608名参与者进行了晚期MDD的大脑表观基因组关联研究（EWAS）。 dPFC）使用Illumina HumanMethylation450 Beadchip阵列生成。我们还分别对男女进行了MDD的EWAS。结果：我们发现基于脑组织的DNA甲基化与晚期MDD之间存在表观基因组范围的显着关联。发现与YOD1基因座中甲基化水平改变有关的最显着且最可靠的关联（cg25594636，p值= 2.55 x 10^-11 ; cg03899372，p值＝ 3.12×10 ^-09；cg12796440，p值= 1.51 x 10 ^-08，cg23982678，p值= 7.94 x 10 ^-08）。分析差异甲基化区域（DMR，p值＝ 5.06×10 ^-10）进一步证实了该基因座。其他重要位点包括UGT8（cg18921206，p-值= 1.75 x 10 ^-08），FNDC3B（cg20367479，p-值= 4.97 x 10 ^-08）和SLIT2（cg10946669，p-值= 8.01 x 10 ^-08））。值得注意的是，与女性相比，男性基于脑组织的甲基化水平与晚期MDD的相关性更高。结论：我们确定了在YOD1，UGT8，FNDC3B和SLIT2基因座中甲基化的改变是与晚年MDD相关的新的表观遗传因素。此外，我们的研究突出了MDD的性别特异性分子异质性。