title: 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.
authors: Psychiatric and Neurodevelopmental Genetics Unit , Massachusetts General Hospital, Boston, Massachusetts; Harvard School of Public Health, Boston, Massachusetts. Electronic address: jsmoller@hms.harvard.edu.
authors: Jordan W
authors: JW
authors: Smoller
authors: Psychiatric and Neurodevelopmental Genetics Unit , Massachusetts General Hospital, Boston, Massachusetts.
authors: Patience J
authors: PJ
authors: Gallagher
authors: 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.
authors: Laramie E
authors: LE
authors: Duncan
authors: Psychiatric and Neurodevelopmental Genetics Unit , Massachusetts General Hospital, Boston, Massachusetts.
authors: Lauren M
authors: LM
authors: McGrath
authors: Psychiatric and Neurodevelopmental Genetics Unit , Massachusetts General Hospital, Boston, Massachusetts.
authors: Stephen A
authors: SA
authors: Haddad
authors: 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.
authors: Avram J
authors: AJ
authors: Holmes
authors: Psychiatric and Neurodevelopmental Genetics Unit , Massachusetts General Hospital, Boston, Massachusetts.
authors: Aaron B
authors: AB
authors: Wolf
authors: Psychiatric and Neurodevelopmental Genetics Unit , Massachusetts General Hospital, Boston, Massachusetts; Harvard College, Harvard University, Boston, Massachusetts.
authors: Sidney
authors: S
authors: Hilker
authors: Department of Psychology, University of Michigan, Ann Arbor, Michigan.
authors: Stefanie R
authors: SR
authors: Block
authors: Psychiatric and Neurodevelopmental Genetics Unit , Massachusetts General Hospital, Boston, Massachusetts.
authors: Sydney
authors: S
authors: Weill
authors: McClean Hospital, Belmont Massachusetts; Massachusetts School of Professional Psychology, Boston, Massachusetts.
authors: Sarah
authors: S
authors: Young
authors: Department of Psychology, Center for Brain Science, Boston, Massachusetts.
authors: Eun Young
authors: EY
authors: Choi
authors: Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
authors: Jerrold F
authors: JF
authors: Rosenbaum
authors: Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts.
authors: Joseph
authors: J
authors: Biederman
authors: Departments of Psychiatry and Neuroscience and Physiology, State University of New York Upstate Medical University, Syracuse, New York.
authors: Stephen V
authors: SV
authors: Faraone
authors: Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, Massachusetts.
authors: Joshua L
authors: JL
authors: Roffman
authors: 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.
authors: Gisele G
authors: GG
authors: Manfro
authors: Department of Psychiatry, Universidade Federal de Ciencias da Saude de Porto Alegre, Porto Alegre, Brazil.
authors: Carolina
authors: C
authors: Blaya
authors: Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
authors: Dina R
authors: DR
authors: Hirshfeld-Becker
authors: Departments of Psychiatry and Family and Preventive Medicine, University of California San Diego, La Jolla, California.
authors: Murray B
authors: MB
authors: Stein
authors: Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada.
authors: Michael
authors: M
authors: Van Ameringen
authors: The Institute of Living, Hartford Hospital, Hartford, Connecticut; Yale University School of Medicine, New Haven, Connecticut.
authors: David F
authors: DF
authors: Tolin
authors: Department of Psychology, Boston University, Boston, Massachusetts.
authors: Michael W
authors: MW
authors: Otto
authors: Department of Psychiatry, Rush University Medical Center, Chicago, Illinois.
authors: Mark H
authors: MH
authors: Pollack
authors: Center for Anxiety and Traumatic Stress Disorders, Massachusetts General Hospital, Boston, Massachusetts.
authors: Naomi M
authors: NM
authors: Simon
authors: Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, Massachusetts; Department of Psychology, Center for Brain Science, Boston, Massachusetts.
authors: Randy L
authors: RL
authors: Buckner
authors: Harvard Medical School, Boston, Massachusetts; McClean Hospital, Belmont Massachusetts.
authors: Dost
authors: D
authors: Ongür
authors: Harvard Medical School, Boston, Massachusetts; McClean Hospital, Belmont Massachusetts.
authors: Bruce M
authors: BM
authors: Cohen
mesh_terms: D062565:Acid Sensing Ion Channels / Q000235:genetics*; D000328:Adult; D000679:Amygdala / Q000473:pathology* / Q000503:physiopathology*; D001931:Brain Mapping; D016022:Case-Control Studies; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D016584:Panic Disorder / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide
chemical_list: C568266:ASIC1 protein, human; D062565:Acid Sensing Ion Channels
keywords: ACCN2; ASIC1a; amygdala; association; genetic; panic disorder