The human ortholog of acid-sensing ion channel gene ASIC1a is associated with panic disorder and amygdala structure and function

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.

Keywords: ACCN2; ASIC1a; amygdala; association; genetic; panic disorder.

Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

Case-Control CONSORT diagram. Ascertainment of cases and controls for the association analysis of ACCN2 variants and panic disorder

Figure 2

Genomic position and LD relationships among ACCN2 SNP positions relative to ACCN2 gene with LD plot and significance denoted. ** Denotes corrected p-value <0.05. Numerical values within the blocks represent D’. The color scale within the blocks represent r2 values: white corresponds to r2=0, shades of gray correspond to 0 < r2 < 1, and black corresponds to r2=1. The r2 between rs685012 and rs10875995 is 0.828.

Figure 3

MDS Plot of Ancestry Informative Markers for Cases and Controls. The first two dimensions of variation generated by the MDS analysis of the AIMs SNPs (for each individual) are plotted on the x and y coordinates of the figure. The cases (blue dots) and controls (orange dots) included in the primary case/control analyses for this project are shown in comparison with the HapMap Phase 3 reference populations. The figure demonstrates that the panic case and control clusters overlap with one another and the HapMap Caucasian reference sample (green circles).

Figure 4

Increased amygdala volume and heightened reactivity in rs10875995 C allele carriers relative to T/T homozygotes. (A) Mean (and SE) amygdala volumes after partialing out variance associated with site, console software version, age, sex, handedness, and ICV. (B) Coronal slice (y=−4) showing task-evoked amygdala reactivity (Faces > Shapes). Color bar reflects T-scores (p