ACMSD methylation in peripheral blood is associated with dynamic functional connectivity pattern in adolescent MDD patients

This study aimed to explore the association between ACMSD methylation level in peripheral blood and brain dynamic functional connectivity (dFC) patterns in adolescents with MDD. Sixty-seven drug-naive, first-episode adolescents with MDD (mean age 14.55 ± 1.38 years, 24 males [35.8%]) and twenty-three healthy controls (HCs, mean age 14.34 ± 1.47 years, 10 males [43.5%]) completed resting-state structural and functional magnetic resonance imaging. DNA samples were collected from peripheral venous blood. Joint and Individual Variation Explained (JIVE) method was used to explore the joint and independent components of four domains of environmental factors (life adverse events, LAE; family environment, FE; family functioning, FF; childhood chronic stress, CCS). Dynamic independent component analysis was used to compute dynamic functional connectivity between brain regions. Associations between ACMSD methylation, environment and brain dFC patterns were assessed. JIVE calculated one joint (JIVE-joint) and seven individual components (JIVE-LAE-1, JIVE-FE-1, JIVE-FE-2, JIVE-FF-1, JIVE-FF-2, JIVE-CCS-1, and JIVE-CCS-2). ACMSD methylation was negatively correlated with JIVE-joint (<i>r</i> = -0.304, <i>p</i> = 0.012) and JIVE-CCS-1 (<i>r</i> = -0.299, <i>p</i> = 0.014) but positively correlated with JIVE-CCS-2 (<i>r</i> = 0.248, <i>p</i> = 0.043). Greater ACMSD methylation was associated with increased dFC strength between the left lateral occipital cortex and right postcentral gyrus (PostCG; T[65] = 4.02, <i>p</i> < 0.001, <i>p</i>-FDR = 0.010) and between the left temporal occipital fusiform cortex and right PostCG (T[65] = 3.86, <i>p</i> < 0.001, <i>p</i>-FDR = 0.035) in adolescent MDD patients. Methylation value of the ACMSD gene is more likely to be influenced by childhood chronic stress. This study may provided a new perspective for future epigenetic research on adolescent MDD.