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. 2022 Apr 27;14(1):55.
doi: 10.1186/s13148-022-01274-y.

Effects of stressful life-events on DNA methylation in panic disorder and major depressive disorder

Darina Czamara  1 , Alexa Neufang  2 , Roman Dieterle  2 , Stella Iurato  3 , Janine Arloth  3 , Jade Martins  3 , Marcus Ising  3 , Elisabeth E Binder  3   4 , Angelika Erhardt  3   5
Affiliations

Effects of stressful life-events on DNA methylation in panic disorder and major depressive disorder

Darina Czamara et al. Clin Epigenetics. .

Abstract

Background: Panic disorder (PD) is characterized by recurrent panic attacks and higher affection of women as compared to men. The lifetime prevalence of PD is about 2-3% in the general population leading to tremendous distress and disability. Etiologically, genetic and environmental factors, such as stress, contribute to the onset and relapse of PD. In the present study, we investigated epigenome-wide DNA methylation (DNAm) in respond to a cumulative, stress-weighted life events score (wLE) in patients with PD and its boundary to major depressive disorder (MDD), frequently co-occurring with symptoms of PD.

Methods: DNAm was assessed by the Illumina HumanMethylation450 BeadChip. In a meta-analytic approach, epigenome-wide DNAm changes in association with wLE were first analyzed in two PD cohorts (with a total sample size of 183 PD patients and 85 healthy controls) and lastly in 102 patients with MDD to identify possible overlapping and opposing effects of wLE on DNAm. Additionally, analysis of differentially methylated regions (DMRs) was conducted to identify regional clusters of association.

Results: Two CpG-sites presented with p-values below 1 × 10-05 in PD: cg09738429 (p = 6.40 × 10-06, located in an intergenic shore region in next proximity of PYROXD1) and cg03341655 (p = 8.14 × 10-06, located in the exonic region of GFOD2). The association of DNAm at cg03341655 and wLE could be replicated in the independent MDD case sample indicating a diagnosis independent effect. Genes mapping to the top hits were significantly upregulated in brain and top hits have been implicated in the metabolic system. Additionally, two significant DMRs were identified for PD only on chromosome 10 and 18, including CpG-sites which have been reported to be associated with anxiety and other psychiatric phenotypes.

Conclusion: This first DNAm analysis in PD reveals first evidence of small but significant DNAm changes in PD in association with cumulative stress-weighted life events. Most of the top associated CpG-sites are located in genes implicated in metabolic processes supporting the hypothesis that environmental stress contributes to health damaging changes by affecting a broad spectrum of systems in the body.

Keywords: EWAS; Major depressive disorder; Panic disorder; Stressful life events.

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Conflict of interest statement

EB is the coinventor of FKBP5: a novel target for antidepressant therapy, European Patent no. EP 1687443 B1, and receives a research grant from Böhringer Ingelheim for a collaboration on functional investigations of FKBP5. It has to be noted that SI is now a full-time employee at Roche Diagnostics GmbH and JM is a full-time employee at Capgemini Deutschland GmbH. Otherwise, the authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Scatterplots for top hits of meta-analysis on EWAS in PD discovery and PD replication sample. Scatter plot of M-value of cg03341655 (y-axis) and log(wLE) (x-axis) in PD discovery (left) and replication sample (right) (A). Scatter plot of M-value of cg09738429 (y-axis) and log(wLE) (x-axis) in PD discovery (left) and replication sample (right) (B)
Fig. 2
Fig. 2
Scatterplots for top DMRs of meta-analysis on EWAS in PD discovery and PD replication sample. Scatter plot of mean M-value of DMR I at chr 10: 10,1282,726–101,282,884 (y-axis) and log( wLE) (x-axis) in PD discovery (left) and replication sample (right) (A). Scatter plot of mean M-value of DMR II at chr 18:72,837,531–72,837,701 (y-axis) and log(wLE) (x-axis) in PD discovery (left) and replication sample (right) (D)
See this image and copyright information in PMC

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