Major depression (MD) is a debilitating mental health condition with peak prevalence occurring early in life. Genome-wide examination of DNA methylation (DNAm) offers an attractive complement to studies of allelic risk given it can reflect the combined influence of genes and environment. The current study used monozygotic twins to identify differentially and variably methylated regions of the genome that distinguish twins with and without a lifetime history of early-onset MD. The sample included 150 Caucasian monozygotic twins between the ages of 15 and 20 (73% female; Mage = 17.52 SD = 1.28) who were assessed during a developmental stage characterized by relatively distinct neurophysiological changes. All twins were generally healthy and currently free of medications with psychotropic effects. DNAm was measured in peripheral blood cells using the Infinium Human BeadChip 450 K Array. MD associations with early-onset MD were detected at 760 differentially and variably methylated probes/regions that mapped to 428 genes. Genes and genomic regions involved neural circuitry formation, projection, functioning, and plasticity. Gene enrichment analyses implicated genes related to neuron structures and neurodevelopmental processes including cell–cell adhesion genes (e.g., PCDHA genes). Genes previously implicated in mood and psychiatric disorders as well as chronic stress (e.g., NRG3) also were identified. DNAm regions associated with early-onset MD were found to overlap genetic loci identified in the latest Psychiatric Genomics Consortium meta-analysis of depression. Understanding the time course of epigenetic influences during emerging adulthood may clarify developmental phases where changes in the DNA methylome may modulate individual differences in MD risk.

重度抑郁症 (MD) 是一种使人衰弱的心理健康状况，其患病率高峰发生在生命早期。DNA 甲基化 (DNAm) 的全基因组检查为等位基因风险研究提供了有吸引力的补充，因为它可以反映基因和环境的综合影响。目前的研究使用同卵双胞胎来识别基因组的差异和可变甲基化区域，以区分有和没有早发性 MD 终生病史的双胞胎。样本包括 150 名 15 至 20 岁的白种人同卵双胞胎（73% 为女性；M年龄 = 17.52  SD = 1.28）在以相对明显的神经生理变化为特征的发育阶段进行评估。所有双胞胎总体上都很健康，目前没有服用具有精神药物作用的药物。使用 Infinium Human BeadChip 450 K Array 在外周血细胞中测量 DNAm。在映射到 428 个基因的 760 个差异和可变甲基化探针/区域检测到 MD 与早发性 MD 的关联。基因和基因组区域涉及神经回路的形成、投射、功能和可塑性。基因富集分析涉及与神经元结构和神经发育过程相关的基因，包括细胞-细胞粘附基因（例如，PCDHA 基因）。先前与情绪和精神疾病以及慢性压力有关的基因（例如，NRG3) 也被识别。发现与早发性 MD 相关的 DNAm 区域与最新的精神病基因组学联盟对抑郁症的荟萃分析中确定的基因位点重叠。了解成年后表观遗传影响的时间过程可能会阐明发育阶段，其中 DNA 甲基化组的变化可能会调节 MD 风险的个体差异。