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The DNA methylome in panic disorder: a case-control and longitudinal psychotherapy-epigenetic study.

ABSTRACT: In panic disorder (PD), epigenetic mechanisms such as DNA methylation of candidate genes have been suggested to play a key role at the intersection of genetic and environmental factors. On an epigenome-wide level, however, only two studies in PD patients have been published so far, while to date no study has intra-individually analyzed dynamic epigenetic correlates of treatment-response in PD on a DNA methylome level. Here, an epigenome-wide association study (EWAS) was performed in a sample of 57 PD patients and matched healthy controls using the Illumina MethylationEPIC BeadChip, along with a longitudinal approach assessing changes on the DNA methylome level corresponding to clinical effects of a manualized six-week cognitive-behavioral therapy (CBT) in PD. While no epigenome-wide significant hits could be discerned, top suggestive evidence was observed for decreased methylation in PD at cg19917903 in the Cilia and Flagella Associated Protein 46 (CFAP46) gene, and for an increase in methylation after CBT at cg06943668 in the Interleukin 1 Receptor Type 1 (IL1R1) gene in treatment responders to CBT. Additional exploratory analyses based on biological validity and a combined statistical/biological ranking point to further new potential PD risk genes such as the CCL4L1 or GMNN genes, and suggest dynamic methylation of, e.g., the ZFP622 and the SLC43A2 genes along with response to CBT. These EWAS and first longitudinal epigenome-wide pilot data in PD add to the emerging candidate gene-based body of evidence for epigenetic mechanisms to be involved in PD pathogenesis and to possibly constitute dynamic biological correlates of therapeutic interventions.

SUBMITTER: Ziegler C

PROVIDER: S-EPMC6872551 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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The DNA methylome in panic disorder: a case-control and longitudinal psychotherapy-epigenetic study.

Ziegler Christiane C Grundner-Culemann Franziska F Schiele Miriam A MA Schlosser Pascal P Kollert Leonie L Mahr Marina M Gajewska Agnieszka A Lesch Klaus-Peter KP Deckert Jürgen J Köttgen Anna A Domschke Katharina K

Translational psychiatry 20191121 1

In panic disorder (PD), epigenetic mechanisms such as DNA methylation of candidate genes have been suggested to play a key role at the intersection of genetic and environmental factors. On an epigenome-wide level, however, only two studies in PD patients have been published so far, while to date no study has intra-individually analyzed dynamic epigenetic correlates of treatment-response in PD on a DNA methylome level. Here, an epigenome-wide association study (EWAS) was performed in a sample of ...[more]

PMID: 31754096

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Project description:BackgroundPanic disorder with or without agoraphobia is a commonly occurring disorder affecting 2 to 3% of the population in Sweden. Untreated, panic disorder is a chronic condition that significantly increases the risk for psychiatric comorbidity, morbidity and mortality, employment difficulties, and healthcare utilization. Cognitive behavioral approaches are the recommended first-line treatment for panic disorder; however, many patients in routine care receive another evidence-based psychotherapy, including psychodynamic therapy. Allowing patients to choose among evidence-based approaches to panic disorder may improve outcomes and reduce overall health costs. Trials comparing the 'gold standard' treatment for panic disorder to other evidence-based psychotherapies are needed, and also trials that can separate patient preferences for treatment from randomization effects on outcome, disability and healthcare utilization in the longer term.Methods/designA phase 2/3 doubly-randomized controlled trial carried out in routine care with 216 adults (aged 18 to 70 years) with a primary diagnosis of DSM-IV Panic Disorder (with or without Agoraphobia). Within each clinic, patients are randomized to self-selection, random assignment of treatment, or wait-list. Patients choose or are randomly assigned to either Panic Control Treatment or Panic-Focused Psychodynamic Psychotherapy. Primary outcomes are changes in panic symptom severity, occupational status, and sickness-related absences from work at post-treatment and 6, 12 and 24 months post-treatment. Secondary outcomes include changes in agoraphobic avoidance, psychiatric comorbidity, disability, and healthcare utilization. The study also employs elements of an effectiveness trial as therapist and service-related effects on outcome will be estimated. Putative change mechanisms for the two treatments are also assessed.DiscussionCognitive behavioral and psychodynamic therapies are both evidence-based approaches that are routinely offered to panic disordered patients in Sweden. However, little is known about the relative effectiveness of these two approaches for panic/agoraphobia, work-related disability and healthcare utilization over the longer term. The current trial (POSE) also addresses the important but understudied issue of whether patient preference for a particular psychotherapeutic approach moderates outcome.Trial registrationClinicalTrials.gov NCT01606592 (registered 19 March 2012).

Project description: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.

Dataset Information

The DNA methylome in panic disorder: a case-control and longitudinal psychotherapy-epigenetic study.

Publications

The DNA methylome in panic disorder: a case-control and longitudinal psychotherapy-epigenetic study.

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