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ABSTRACT: Background
Individuals with panic disorder (PD) exhibit a hypersensitivity to inhaled carbon dioxide, possibly reflecting a lowered threshold for sensing signals of suffocation. Animal studies have shown that carbon dioxide-mediated fear behavior depends on chemosensing of acidosis in the amygdala via the acid-sensing ion channel ASIC1a. We examined whether the human ortholog of the ASIC1a gene, ACCN2, is associated with the presence of PD and with amygdala structure and function.Methods
We conducted a case-control analysis (n = 414 PD cases and 846 healthy controls) of ACCN2 single nucleotide polymorphisms and PD. We then tested whether variants showing significant association with PD are also associated with amygdala volume (n = 1048) or task-evoked reactivity to emotional stimuli (n = 103) in healthy individuals.Results
Two single nucleotide polymorphisms at the ACCN2 locus showed evidence of association with PD: rs685012 (odds ratio = 1.32, gene-wise corrected p = .011) and rs10875995 (odds ratio = 1.26, gene-wise corrected p = .046). The association appeared to be stronger when early-onset (age ≤ 20 years) PD cases and when PD cases with prominent respiratory symptoms were compared with controls. The PD risk allele at rs10875995 was associated with increased amygdala volume (p = .035) as well as task-evoked amygdala reactivity to fearful and angry faces (p = .0048).Conclusions
Genetic variation at ACCN2 appears to be associated with PD and with amygdala phenotypes that have been linked to proneness to anxiety. These results support the possibility that modulation of acid-sensing ion channels may have therapeutic potential for PD.
SUBMITTER: Smoller JW
PROVIDER: S-EPMC4103972 | biostudies-literature | 2014 Dec
REPOSITORIES: biostudies-literature
Smoller Jordan W JW Gallagher Patience J PJ Duncan Laramie E LE McGrath Lauren M LM Haddad Stephen A SA Holmes Avram J AJ Wolf Aaron B AB Hilker Sidney S Block Stefanie R SR Weill Sydney S Young Sarah S Choi Eun Young EY Rosenbaum Jerrold F JF Biederman Joseph J Faraone Stephen V SV Roffman Joshua L JL Manfro Gisele G GG Blaya Carolina C Hirshfeld-Becker Dina R DR Stein Murray B MB Van Ameringen Michael M Tolin David F DF Otto Michael W MW Pollack Mark H MH Simon Naomi M NM Buckner Randy L RL Ongür Dost D Cohen Bruce M BM
Biological psychiatry 20140118 11
<h4>Background</h4>Individuals with panic disorder (PD) exhibit a hypersensitivity to inhaled carbon dioxide, possibly reflecting a lowered threshold for sensing signals of suffocation. Animal studies have shown that carbon dioxide-mediated fear behavior depends on chemosensing of acidosis in the amygdala via the acid-sensing ion channel ASIC1a. We examined whether the human ortholog of the ASIC1a gene, ACCN2, is associated with the presence of PD and with amygdala structure and function.<h4>Met ...[more]