Genome-wide Profiling of DNA Methylome and Transcriptome in Peripheral Blood Monocytes for Major Depression: A Monozygotic Discordant Twin Study

Major depressive disorder (MDD) is one of the most prevalent worldwide psychiatric disorders. Epigenetic mechanisms are thought to be involved in MDD, but the specific genes or genomic regions associated with MDD remain... [ view full abstract ]

Major depressive disorder (MDD) is one of the most prevalent worldwide psychiatric disorders. Epigenetic mechanisms are thought to be involved in MDD, but the specific genes or genomic regions associated with MDD remain largely unknown. Here we conducted an epigenome-wide association study (EWAS) using the Illumina HumanMethylation450 BeadChip in peripheral blood monocytes from 47 monozygotic (MZ) twin pairs discordant for MDD. We identified 406 probes that were differentially methylated between depressed twins and their non-depressed co-twins. Region-based analysis identified 16 differentially methylated regions (DMRs) significantly associated with MDD at the level of FDR-adjusted P <0.05. These putative DMRs harbor candidate genes previously reported to be associated with MDD, and also several new loci containing genes involved in synaptic transmission or neurological functions. To determine the functional importance of DNA methylation alteration in gene regulation, we also performed genome-wide transcriptome analysis in blood monocytes of the same twins. Integrated analysis revealed both negative and positive correlations between DNA methylation and gene expression. A systems biology approach that combines gene co-methylation network with functional enrichment analysis elucidated distinct modules enriched with genes involved in neurotransmission or brain functions. Together, our results confirmed the role of DNA methylation in depression. Moreover, our study demonstrated that a well-designed monozygotic discordant co-twin control design could aid the discovery of novel DNA methylation signals, even in a limited sample size.