Jordan W Smoller1, Patience J Gallagher2, Laramie E Duncan3, Lauren M McGrath2, Stephen A Haddad2, Avram J Holmes4, Aaron B Wolf2, Sidney Hilker5, Stefanie R Block6, Sydney Weill2, Sarah Young7, Eun Young Choi8, Jerrold F Rosenbaum9, Joseph Biederman10, Stephen V Faraone11, Joshua L Roffman12, Gisele G Manfro13, Carolina Blaya14, Dina R Hirshfeld-Becker9, Murray B Stein15, Michael Van Ameringen16, David F Tolin17, Michael W Otto18, Mark H Pollack19, Naomi M Simon20, Randy L Buckner21, Dost Ongür22, Bruce M Cohen22. 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.
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: Bruce Fischl; David H Salat; Evelina Busa; Marilyn Albert; Megan Dieterich; Christian Haselgrove; Andre van der Kouwe; Ron Killiany; David Kennedy; Shuna Klaveness; Albert Montillo; Nikos Makris; Bruce Rosen; Anders M Dale Journal: Neuron Date: 2002-01-31 Impact factor: 17.173
Authors: Ellen A A van der Plas; Aaron D Boes; John A Wemmie; Daniel Tranel; Peg Nopoulos Journal: Soc Cogn Affect Neurosci Date: 2010-02-11 Impact factor: 3.436
Authors: John A Wemmie; Candice C Askwith; Ejvis Lamani; Martin D Cassell; John H Freeman; Michael J Welsh Journal: J Neurosci Date: 2003-07-02 Impact factor: 6.167
Authors: John M Hettema; Seon-Sook An; Michael C Neale; Edwin J C G van den Oord; Kenneth S Kendler; Xiangning Chen Journal: Psychiatr Genet Date: 2008-04 Impact factor: 2.458
Authors: Ahmad R Hariri; Venkata S Mattay; Alessandro Tessitore; Bhaskar Kolachana; Francesco Fera; David Goldman; Michael F Egan; Daniel R Weinberger Journal: Science Date: 2002-07-19 Impact factor: 47.728
Authors: Adam E Ziemann; Jason E Allen; Nader S Dahdaleh; Iuliia I Drebot; Matthew W Coryell; Amanda M Wunsch; Cynthia M Lynch; Frank M Faraci; Matthew A Howard; Michael J Welsh; John A Wemmie Journal: Cell Date: 2009-11-25 Impact factor: 41.582
Authors: Justin S Feinstein; Colin Buzza; Rene Hurlemann; Robin L Follmer; Nader S Dahdaleh; William H Coryell; Michael J Welsh; Daniel Tranel; John A Wemmie Journal: Nat Neurosci Date: 2013-02-03 Impact factor: 24.884
Authors: A S Howe; H N Buttenschøn; A Bani-Fatemi; E Maron; T Otowa; A Erhardt; E B Binder; N O Gregersen; O Mors; D P Woldbye; K Domschke; A Reif; J Shlik; S Kõks; Y Kawamura; A Miyashita; R Kuwano; K Tokunaga; H Tanii; J W Smoller; T Sasaki; D Koszycki; V De Luca Journal: Mol Psychiatry Date: 2015-09-22 Impact factor: 15.992
Authors: Jennifer A Sumner; Abigail Powers; Tanja Jovanovic; Karestan C Koenen Journal: Am J Med Genet B Neuropsychiatr Genet Date: 2015-09-17 Impact factor: 3.568
Authors: Jeanne E Savage; Omari McMichael; Eugenia I Gorlin; Jessica R Beadel; Bethany Teachman; Vladimir I Vladimirov; John M Hettema; Roxann Roberson-Nay Journal: Biol Psychol Date: 2015-04-22 Impact factor: 3.251
Authors: Jeanne E Savage; Chelsea Sawyers; Roxann Roberson-Nay; John M Hettema Journal: Am J Med Genet B Neuropsychiatr Genet Date: 2016-05-19 Impact factor: 3.568
Authors: Rebecca J Taugher; Yuan Lu; Yimo Wang; Collin J Kreple; Ali Ghobbeh; Rong Fan; Levi P Sowers; John A Wemmie Journal: J Neurosci Date: 2014-07-30 Impact factor: 6.167
Authors: Ali Ghobbeh; Rebecca J Taugher; Syed M Alam; Rong Fan; Ryan T LaLumiere; John A Wemmie Journal: Genes Brain Behav Date: 2018-11-28 Impact factor: 3.449