Hypermethylation in the ZBTB20 gene is associated with major depressive disorder

Abstract

Background: Although genetic variation is believed to contribute to an individual's susceptibility to major depressive disorder, genome-wide association studies have not yet identified associations that could explain the full etiology of the disease. Epigenetics is increasingly believed to play a major role in the development of common clinical phenotypes, including major depressive disorder.

Results: Genome-wide MeDIP-Sequencing was carried out on a total of 50 monozygotic twin pairs from the UK and Australia that are discordant for depression. We show that major depressive disorder is associated with significant hypermethylation within the coding region of ZBTB20, and is replicated in an independent cohort of 356 unrelated case-control individuals. The twins with major depressive disorder also show increased global variation in methylation in comparison with their unaffected co-twins. ZBTB20 plays an essential role in the specification of the Cornu Ammonis-1 field identity in the developing hippocampus, a region previously implicated in the development of major depressive disorder.

Conclusions: Our results suggest that aberrant methylation profiles affecting the hippocampus are associated with major depressive disorder and show the potential of the epigenetic twin model in neuro-psychiatric disease.

Figure 1

Genomic methylation profiles of a female monozygotic twin pair discordant for major depressive disorder (MeDIP-seq data of depressed and non-depressed twin shown in red and green, respectively). Although the overall patterns are extremely similar, differential methylation does occur at specific loci.

Figure 2

Manhattan plot showing the P- values of approximately 10 M 500 bp bins from the meta analysis with the ZBTB20 DMR identified in the plot.

Figure 3

(A,B) Replication of differentially methylated genes in an independent case-control cohort of 118 depressed and 236 control unrelated females. The plot shows significantly increased methylation levels of the ZBTB20 DMR region in individuals with MDD. (C) Case versus control RPM counts for the DMR of ZBTB20 in 50 MZ twin pairs discordant for MDD.

Figure 4

Weighted gene co-expression networks using WGCNA showing unique co-expression of ZBTB20 in the hippocampus from a module containing 216 genes.