Epigenome-wide association study of DNA methylation in panic disorder

Abstract

BackgroundPanic disorder (PD) is considered to be a multifactorial disorder emerging from interactions among multiple genetic and environmental factors. To date, although genetic studies reported several susceptibility genes with PD, few of them were replicated and the pathogenesis of PD remains to be clarified. Epigenetics is considered to play an important role in etiology of complex traits and diseases, and DNA methylation is one of the major forms of epigenetic modifications. In this study, we performed an epigenome-wide association study of PD using DNA methylation arrays so as to investigate the possibility that different levels of DNA methylation might be associated with PD.MethodsThe DNA methylation levels of CpG sites across the genome were examined with genomic DNA samples (PD, N = 48, control, N = 48) extracted from peripheral blood. Methylation arrays were used for the analysis. β values, which represent the levels of DNA methylation, were normalized via an appropriate pipeline. Then, β values were converted to M values via the logit transformation for epigenome-wide association study. The relationship between each DNA methylation site and PD was assessed by linear regression analysis with adjustments for the effects of leukocyte subsets.ResultsForty CpG sites showed significant association with PD at 5% FDR correction, though the differences of the DNA methylation levels were relatively small. Most of the significant CpG sites (37/40 CpG sites) were located in or around CpG islands. Many of the significant CpG sites (27/40 CpG sites) were located upstream of genes, and all such CpG sites with the exception of two were hypomethylated in PD subjects. A pathway analysis on the genes annotated to the significant CpG sites identified several pathways, including “positive regulation of lymphocyte activation.”ConclusionsAlthough future studies with larger number of samples are necessary to confirm the small DNA methylation abnormalities associated with PD, there is a possibility that several CpG sites might be associated, together as a group, with PD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0307-1) contains supplementary material, which is available to authorized users.

“DNA Methylation signatures in panic disorder”

“…Notably, the significant changes in DNA methylation presented here are small with less than 1% difference (0.08%) but replicable. While the functional relevance of such small changes is debatable, these effect sizes are in line with other EWAS in psychiatry, including the recent small Japanese EWAS in PD 22 , where 40 significant CpGs with overall low methylation (mostly under 0.05%) differences have been detected. Sex-specific associations were not reported, most likely because of the small sample size.…”

“…To date, a few studies have investigated differences in DNA methylation in candidate genes in PD 5 , 18 – 21 . Recently, one epigenome-wide study of DNA methylation in a relatively small Japanese PD case-control sample (48 patients vs. 48 controls) detected significant associations at 40 sites with overall small methylation differences 22 . So far, studies in the European population are lacking.…”

Assessing Panic: Bridging the Gap Between Fundamental Mechanisms and Daily Life Experience

“…Very recently, the first two epigenome-wide association studies (EWAS) were published. Shimada-Sugimoto et al (2017) found 40 CpG sites that were significantly associated with PD. Most of them were hypomethylated and pathway analysis revealed genes in epidermis development, cell cycle regulation, and lymphocyte activation.…”

A maternal effect regulates global DNA methylation patterns

“…Methylation patterns are known to vary across cell types, where they contribute to the maintenance of cellular identities and to the response to environmental perturbations through the regulation of gene expression (Rakyan et al, 2008;Lister et al, 2009). In the brain, DNA methylation status has been associated with its structure and function (Wheater et al, 2020) and aberrations in methylation profiles, with sub-regional and cell-type specificity (Rizzardi et al, 2019) have been associated with many forms of mental illness (Grayson and Guidotti, 2013;Shimada-Sugimoto et al, 2017;Liu et al, 2018;Li et al, 2019).…”