title: 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.
authors.affiliation: Department of Psychiatry, University of Muenster, Germany; Department of Psychiatry, University of Wuerzburg, Germany. Electronic address: Domschke_K@klinik.uni-wuerzburg.de.
authors.forename: Katharina
authors.initials: K
authors.lastname: Domschke
authors.forename: Nicola
authors.initials: N
authors.lastname: Tidow
authors.forename: Marie
authors.initials: M
authors.lastname: Schrempf
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schwarte
authors.forename: Benedikt
authors.initials: B
authors.lastname: Klauke
authors.forename: Andreas
authors.initials: A
authors.lastname: Reif
authors.forename: Anette
authors.initials: A
authors.lastname: Kersting
authors.forename: Volker
authors.initials: V
authors.lastname: Arolt
authors.forename: Peter
authors.initials: P
authors.lastname: Zwanzger
authors.forename: Jürgen
authors.initials: J
authors.lastname: Deckert
mesh_terms: D000328:Adult; D001483:Base Sequence; D019175:DNA Methylation / Q000502:physiology*; D044127:Epigenesis, Genetic / Q000502:physiology*; D005260:Female; D005968:Glutamate Decarboxylase / Q000502:physiology*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D016584:Panic Disorder / Q000201:enzymology* / Q000235:genetics*; D010865:Pilot Projects; D055815:Young Adult
chemical_list: D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1
keywords: Anxiety; COMT; DNA-methyltransferase 1; DNMT1; Epigenetics; GABA; GAD; GAD1; GAD2; HAB; Methylation; PBMCs; PFC; SME; SNP; SSRIs; catechol-O-methyltransferase; epigenetic sequencing methylation analysis software; gamma-aminobutyric acid; glutamate decarboxylase; high anxiety-related behavior; methQTL; methylation quantitative trait loci; peripheral mononuclear blood cells; prefrontal cortex; selective serotonin inhibitors; single nucleotide polymorphism