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.
Highlights
Panic disorder (PD) is a frequent and highly debilitating mental disorder with a life-time prevalence of 1–3% and women being affected ~2–3 times more often than men[1]
In a proofof-principle, candidate gene-based treatment-epigenetic approach, monoamine oxidase A (MAOA) hypomethylation in patients with panic disorder (PD) has been observed to be reversible by a successful cognitive-behavioral psychotherapeutic intervention in two independent samples, with responders showing an increase in MAOA methylation after treatment, i.e., ‘normalization’ up to methylation levels in healthy controls[8]
Top suggestive evidence was discerned for decreased methylation in PD patients as compared to healthy controls at cg19917903 in the gene coding for the Cilia and Flagella Associated Protein 46 (CFAP46)
Summary
Panic disorder (PD) is a frequent and highly debilitating mental disorder with a life-time prevalence of 1–3% and women being affected ~2–3 times more often than men[1]. Affective and stress-related disorders, epigenetic mechanisms such as DNA methylation have been suggested to play a key role at the intersection of genetic and environmental factors in disease pathogenesis as well as in treatment response mediation Two recent epigenome-wide association studies (EWAS) in PD using the Infinium HumanMethylation[450] BeadChip have suggested hypermethylation of a CpG site in the enhancer region of the homo sapiens headcase homolog (Drosophila) (HECA) gene in 49 European PD patients and an independent replication sample[14], and mostly hypomethylation at 40 CpG sites, in 48 Japanese patients with PD as compared to healthy controls[15]. To the best of our knowledge, a longitudinal study on epigenetic correlates of treatment-response in PD on the DNA methylome level has not been published so far
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