Epigenetic signature of panic disorder: A role of glutamate decarboxylase 1 (GAD1) DNA hypomethylation?
Abstract
Glutamate decarboxylases (GAD67/65; GAD1/GAD2) are crucially involved in gamma-aminobutyric acid (GABA) synthesis and thus were repeatedly suggested to play an important role in the pathogenesis of anxiety disorders. In the present study, DNA methylation patterns in the GAD1 and GAD2 promoter and GAD1 intron 2 regions were investigated for association with panic disorder, with particular attention to possible effects of environmental factors. Sixty-five patients with panic disorder (f=44, m=21) and 65 matched healthy controls were analyzed for DNA methylation status at 38 GAD1 promoter/intron2 and 10 GAD2 promoter CpG sites via direct sequencing of sodium bisulfate treated DNA extracted from blood cells. Recent positive and negative life events were ascertained. Patients and controls were genotyped for GAD1 rs3762556, rs3791878 and rs3762555, all of which are located in the analyzed promoter region. Patients with panic disorder exhibited significantly lower average GAD1 methylation than healthy controls (p<0.001), particularly at three CpG sites in the promoter as well as in intron 2. The occurrence of negative life events was correlated with relatively decreased average methylation mainly in the female subsample (p=0.01). GAD1 SNP rs3762555 conferred a significantly lower methylation at three GAD1 intron 2 CpG sites (p<0.001). No differential methylation was observed in the GAD2 gene. The present pilot data suggest a potentially compensatory role of GAD1 gene hypomethylation in panic disorder possibly mediating the influence of negative life events and depending on genetic variation. Future studies are warranted to replicate the present finding in independent samples, preferably in a longitudinal design.
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GAD1 promoter hypomethylation was significantly negatively correlated with the proportion of exposure to negative life events during the past year in patients and controls, primarily in females.
“This GAD1 promoter hypomethylation was significantly negatively correlated with the proportion of exposure to negative life events during the past year in patients and controls, primarily in females”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as Domschke et al., 2013
Average methylation across CpG islands in the promoter region and the second intron of GAD1 was lower in panic disorder patients compared to healthy controls (n=65 each), with a particularly strong effect in the promoter region.
“average methylation across CpG islands in the promoter region and the second intron of the GAD1 gene (chromosomal location 2q31.1)coding for the glutamate decarboxylase 67, which catalyzes the pyridoxal phosphatedependent decarboxylation of glutamate to GABA, was found to be lower in panic disorder patients compared to healthy controls (n=65 each), with a particularly strong effect in the promoter”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as Domschke et al., 2013
GAD1 methylation is decreased in association with increased negative life events.
“↓ GAD1 methylation associated with increased negative life events”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as Domschke et al., 2013
MAOA methylation is increased in association with increased positive life events.
“↑ MAOA methylation associated with increased positive life events”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as Domschke et al., 2013
One study found that exposure to childhood adversity was associated with decreased DNAm in GAD in a sample of Panic Disorder.
“At the level of the Glutamatergic pathway, one study found that exposure to CA was associated with decreased DNAm in GAD in a sample of Panic Disorder (Domschke et al., 2013).”
From Can epigenetics shine a light on the biological pathways underlying major mental disorders? (2022) · cites this paper as Domschke et al., 2013
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“…→ ↑GRIN2B Engdahl et al. (2021) Candidate gene Saliva General population GRIND1 Weder et al. (2014) EWAS Saliva Trauma/non-trauma children GAD1 Ruzicka et al. (2015) Candidate gene PMB SCZ/BD ↓Domschke et al. (2013) Candidate gene Blood Panic disorder Life events → ↓GAD1 DNAm (Continued ) Table 2.”
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- Authors
- Domschke, K., Tidow, N., Schrempf, M., Schwarte, K., Klauke, B., Reif, A., Kersting, A., Arolt, V., Zwanzger, P., & Deckert, J.
- Affiliations
- University of Münster (DE)
- University of Würzburg (DE)
- Leipzig University (DE)
- Corresponding author
- Domschke, Katharina
- ORCID
- Venue
- Progress in Neuro-Psychopharmacology and Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2013-10
- Volume
- 46
- Pages
- 189-196
- ISSN
- 0278-5846 (ISSN-L)
- OpenAlex
- W2021501413
- Cited by
- 87
- References
- 58
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 3 · 2023: 5 · 2022: 25 · 2021: 2 · 2020: 7 · 2019: 5 · 2018: 5 · 2017: 9 · 2016: 9 · 2015: 8 · 2014: 4
- FWCI
- 3.13
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Progress in Neuro-Psychopharmacology and Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (DFG)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Maternal Mental Health During Pregnancy and Postpartum
- Keywords
- panic disorder, GAD1, DNA hypomethylation, DNA methylation, GABA synthesis, anxiety disorders, negative life events, promoter CpG sites, intron 2, single nucleotide polymorphisms, epigenetics, sex differences
- MeSH terms
- Adult, Base Sequence, Female, Glutamate Decarboxylase, Humans, Male, Molecular Sequence Data, Pilot Projects, Panic Disorder, DNA Methylation, Epigenesis, Genetic, Young Adult
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