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Biol Psychiatry. 2014 Dec 1;76(11):902-10. doi: 10.1016/j.biopsych.2013.12.018. Epub 2014 Jan 18.

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

Author information

1
Psychiatric and Neurodevelopmental Genetics Unit , Massachusetts General Hospital, Boston, Massachusetts; Harvard School of Public Health, Boston, Massachusetts. Electronic address: jsmoller@hms.harvard.edu.
2
Psychiatric and Neurodevelopmental Genetics Unit , Massachusetts General Hospital, Boston, Massachusetts.
3
Psychiatric and Neurodevelopmental Genetics Unit , Massachusetts General Hospital, Boston, Massachusetts; Harvard School of Public Health, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; Broad Institute, Cambridge, Massachusetts.
4
Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, Massachusetts; Department of Psychology, Center for Brain Science, Boston, Massachusetts.
5
Psychiatric and Neurodevelopmental Genetics Unit , Massachusetts General Hospital, Boston, Massachusetts; Harvard College, Harvard University, Boston, Massachusetts.
6
Department of Psychology, University of Michigan, Ann Arbor, Michigan.
7
McClean Hospital, Belmont Massachusetts; Massachusetts School of Professional Psychology, Boston, Massachusetts.
8
Department of Psychology, Center for Brain Science, Boston, Massachusetts.
9
Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
10
Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts.
11
Departments of Psychiatry and Neuroscience and Physiology, State University of New York Upstate Medical University, Syracuse, New York.
12
Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, Massachusetts.
13
Anxiety Disorders Outpatient Program, Hospital de Clínicas de Porto Alegre; Post Graduate Program in Medical Sciences: Psychiatry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
14
Department of Psychiatry, Universidade Federal de Ciencias da Saude de Porto Alegre, Porto Alegre, Brazil.
15
Departments of Psychiatry and Family and Preventive Medicine, University of California San Diego, La Jolla, California.
16
Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada.
17
The Institute of Living, Hartford Hospital, Hartford, Connecticut; Yale University School of Medicine, New Haven, Connecticut.
18
Department of Psychology, Boston University, Boston, Massachusetts.
19
Department of Psychiatry, Rush University Medical Center, Chicago, Illinois.
20
Center for Anxiety and Traumatic Stress Disorders, Massachusetts General Hospital, Boston, Massachusetts.
21
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, Massachusetts; Department of Psychology, Center for Brain Science, Boston, Massachusetts.
22
Harvard Medical School, Boston, Massachusetts; McClean Hospital, Belmont Massachusetts.

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

PMID:
24529281
PMCID:
PMC4103972
DOI:
10.1016/j.biopsych.2013.12.018
[Indexed for MEDLINE]
Free PMC Article

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