title: Candidate genes in panic disorder: meta-analyses of 23 common variants in major anxiogenic pathways.
abstract: The utilization of molecular genetics approaches in examination of panic disorder (PD) has implicated several variants as potential susceptibility factors for panicogenesis. However, the identification of robust PD susceptibility genes has been complicated by phenotypic diversity, underpowered association studies and ancestry-specific effects. In the present study, we performed a succinct review of case-control association studies published prior to April 2015. Meta-analyses were performed for candidate gene variants examined in at least three studies using the Cochrane Mantel-Haenszel fixed-effect model. Secondary analyses were also performed to assess the influences of sex, agoraphobia co-morbidity and ancestry-specific effects on panicogenesis. Meta-analyses were performed on 23 variants in 20 PD candidate genes. Significant associations after correction for multiple testing were observed for three variants, TMEM132D rs7370927 (T allele: odds ratio (OR)=1.27, 95% confidence interval (CI): 1.15-1.40, P=2.49 × 10(-6)), rs11060369 (CC genotype: OR=0.65, 95% CI: 0.53-0.79, P=1.81 × 10(-5)) and COMT rs4680 (Val (G) allele: OR=1.27, 95% CI: 1.14-1.42, P=2.49 × 10(-5)) in studies with samples of European ancestry. Nominal associations that did not survive correction for multiple testing were observed for NPSR1 rs324891 (T allele: OR=1.22, 95% CI: 1.07-1.38, P=0.002), TPH1 rs1800532 (AA genotype: OR=1.46, 95% CI: 1.14-1.89, P=0.003) and HTR2A rs6313 (T allele: OR=1.19, 95% CI: 1.07-1.33, P=0.002) in studies with samples of European ancestry and for MAOA-uVNTR in female PD (low-active alleles: OR=1.21, 95% CI: 1.07-1.38, P=0.004). No significant associations were observed in the secondary analyses considering sex, agoraphobia co-morbidity and studies with samples of Asian ancestry. Although these findings highlight a few associations, PD likely involves genetic variation in a multitude of biological pathways that is diverse among populations. Future studies must incorporate larger sample sizes and genome-wide approaches to further quantify the observed genetic variation among populations and subphenotypes of PD.
authors.affiliation: Neurogenetics Department, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: A S
authors.initials: AS
authors.lastname: Howe
authors.affiliation: Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark.|The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus, Denmark.
authors.forename: H N
authors.initials: HN
authors.lastname: Buttenschøn
authors.affiliation: Neurogenetics Department, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Bani-Fatemi
authors.affiliation: Department of Neuropsychopharmacology and Molecular Imaging, Imperial College London, London, UK.|Department of Psychiatry, University of Tartu, Tartu, Estonia.
authors.forename: E
authors.initials: E
authors.lastname: Maron
authors.affiliation: Department of Neuropsychiatry, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Otowa
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Erhardt
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: E B
authors.initials: EB
authors.lastname: Binder
authors.affiliation: Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark.|The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus, Denmark.
authors.forename: N O
authors.initials: NO
authors.lastname: Gregersen
authors.affiliation: The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus, Denmark.|Research Department P, Aarhus University Hospital, Risskov, Denmark.
authors.forename: O
authors.initials: O
authors.lastname: Mors
authors.affiliation: Laboratory of Neuroplasticity, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: D P
authors.initials: DP
authors.lastname: Woldbye
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Domschke
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, Goethe-University Frankfurt, Frankfurt am Main, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Reif
authors.affiliation: Department of Psychiatry, University of Ottawa, Ottawa, ON, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Shlik
authors.affiliation: Department of Physiology, University of Tartu, Tartu, Estonia.
authors.forename: S
authors.initials: S
authors.lastname: Kõks
authors.affiliation: Department of Psychiatry, Sakae Seijinkai Hospital, Yokohama, Kanagawa, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kawamura
authors.affiliation: Department of Psychiatry, Sakae Seijinkai Hospital, Yokohama, Kanagawa, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Miyashita
authors.affiliation: Department of Molecular Genetics, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Kuwano
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Tokunaga
authors.affiliation: Department of Psychiatry, Division of Neuroscience, Graduate School of Medicine, Brain Science and Animal Model Research Center, Mie University, Tsu, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Tanii
authors.affiliation: Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Smoller
authors.affiliation: Laboratory of Health Education, Graduate School of Education, The University of Tokyo, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Faculty of Education (Counselling), University of Ottawa, Ottawa, ON, Canada.|Faculty of Medicine (Psychiatry), University of Ottawa, Ottawa, Ontario, Canada.|Institut de Recherche de l'Hôpital Montfort, Ottawa, ON, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Koszycki
authors.affiliation: Neurogenetics Department, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Department of Psychiatry, Centre for Addiction and Mental Health, Toronto, Canada.
authors.forename: V
authors.initials: V
authors.lastname: De Luca
mesh_terms: D001007:Anxiety / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D016584:Panic Disorder / Q000235:genetics*; D011110:Polymorphism, Genetic