Genome-wide DNA methylation and gene expression analyses in monozygotic twins identify potential biomarkers of depression

Abstract

Depression is currently the leading cause of disability around the world. We conducted an epigenome-wide association study (EWAS) in a sample of 58 depression score-discordant monozygotic twin pairs, aiming to detect specific epigenetic variants potentially related to depression and further integrate with gene expression profile data. Association between the methylation level of each CpG site and depression score was tested by applying a linear mixed effect model. Weighted gene co-expression network analysis (WGCNA) was performed for gene expression data. The association of DNA methylation levels of 66 CpG sites with depression score reached the level of P < 1 × 10−4. These top CpG sites were located at 34 genes, especially PTPRN2, HES5, GATA2, PRDM7, and KCNIP1. Many ontology enrichments were highlighted, including Notch signaling pathway, Huntington disease, p53 pathway by glucose deprivation, hedgehog signaling pathway, DNA binding, and nucleic acid metabolic process. We detected 19 differentially methylated regions (DMRs), some of which were located at GRIK2, DGKA, and NIPA2. While integrating with gene expression data, HELZ2, PTPRN2, GATA2, and ZNF624 were differentially expressed. In WGCNA, one specific module was positively correlated with depression score (r = 0.62, P = 0.002). Some common genes (including BMP2, PRDM7, KCNIP1, and GRIK2) and enrichment terms (including complement and coagulation cascades pathway, DNA binding, neuron fate specification, glial cell differentiation, and thyroid gland development) were both identified in methylation analysis and WGCNA. Our study identifies specific epigenetic variations which are significantly involved in regions, functional genes, biological function, and pathways that mediate depression disorder.

Identification of potential Mitogen-Activated Protein Kinase-related key genes and regulation networks in molecular subtypes of major depressive disorder

“…The common transcription factors were GATA2, FLI1, CREB1, JUND, E2F1, ESR1, TRAP4, SP1, and GABPA. It has been reported that GATA2, CREB1, and E2F1 were crucial in the maintenance of MDD (41)(42)(43). And ESR1, an estrogen receptor, was also found to be important in depression (44).…”

Bioinformatic analysis and experimental validation identified DNA methylation–Related biomarkers and immune-cell infiltration of atherosclerosis

“…The aberrant expression of GRIK2 has been reported to be involved in regions, functional genes, biological function, and pathways that mediate depression disorder. GRIK2 also showed abnormal methylation pattern specific to astrocytic dysfunction associated with depressive psychopathology ( Nagy et al, 2015 ; Wang W. et al, 2021 ). It is interesting to explore the potential association of AS with the nervous system.…”

Brain-Derived Neurotrophic Factor (BDNF) Epigenomic Modifications and Brain-Related Phenotypes in Humans: A Systematic Review

“…Recent large-scale genome-wide association studies have failed to replicate some of the BDNF genetic associations from earlier candidate gene studies (Border et al, 2019; Johnson et al, 2017). Although EWASs are several years behind, emerging evidence indicates similar replication issues for candidate DNAm studies in brain-related phenotypes (Shields et al, 2021; Sumner et al, 2022; Wang et al, 2021). Consistent with the recent recommendations of the National Institute of Mental Health Council Workgroup on Genomics (Hyman and Krystal, 2018), we recommend that candidate DNAm studies should be abandoned for EWAS approaches in most cases.…”