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

Weijing Wang,Qihua Tan,Yili Wu,Dongfeng Zhang,Shuxia Li,Weilong Li,Xiaocao Tian,Haiping Duan

doi:10.1038/s41398-021-01536-y

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.

Highlights

Depression is currently the leading cause of disability worldwide [1], and it is predicted to be one of the three leading causes of illness by 2030 [2]
Epigenome-wide association analysis As shown in the Manhattan plot (Fig. 1) and Table 2, the association of DNA methylation levels of 66 top CpG sites with depression score reached the level of P < 1 × 10−4
The numbers of these top CpG sites located at chr1, chr4, chr16, chr19, chr20, chr11, chr7, chr6, chr12, and chr17 were 9, 8, 7, 6, 6, 5, 5, 4, 3, and 3, respectively

Summary

Introduction

Depression is currently the leading cause of disability worldwide [1], and it is predicted to be one of the three leading causes of illness by 2030 [2]. The depression risk is influenced by both genetic and environmental factors. It is suggested that epigenetic modification could mediate the lasting increasing depression risk resulting from exposure to adverse life events and provide a mechanistic framework, where genetic and environmental factors were integrated [3, 4]. DNA methylation was one important form of epigenetic modification, and one recent review of 67 studies concluded that there was evidence for the association of DNA methylation variation with depression risk [5]. Even currently some significant methylation modifications were found to be associated with depression, no consistent results were identified

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Results

Conclusion