title: Meta-analysis of genome-wide association studies of anxiety disorders.
abstract: Anxiety disorders (ADs), namely generalized AD, panic disorder and phobias, are common, etiologically complex conditions with a partially genetic basis. Despite differing on diagnostic definitions based on clinical presentation, ADs likely represent various expressions of an underlying common diathesis of abnormal regulation of basic threat-response systems. We conducted genome-wide association analyses in nine samples of European ancestry from seven large, independent studies. To identify genetic variants contributing to genetic susceptibility shared across interview-generated DSM-based ADs, we applied two phenotypic approaches: (1) comparisons between categorical AD cases and supernormal controls, and (2) quantitative phenotypic factor scores (FS) derived from a multivariate analysis combining information across the clinical phenotypes. We used logistic and linear regression, respectively, to analyze the association between these phenotypes and genome-wide single nucleotide polymorphisms. Meta-analysis for each phenotype combined results across the nine samples for over 18 000 unrelated individuals. Each meta-analysis identified a different genome-wide significant region, with the following markers showing the strongest association: for case-control contrasts, rs1709393 located in an uncharacterized non-coding RNA locus on chromosomal band 3q12.3 (P=1.65 × 10(-8)); for FS, rs1067327 within CAMKMT encoding the calmodulin-lysine N-methyltransferase on chromosomal band 2p21 (P=2.86 × 10(-9)). Independent replication and further exploration of these findings are needed to more fully understand the role of these variants in risk and expression of ADs.
authors.affiliation: Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.|Department of Neuropsychiatry, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Otowa
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.|Department of Psychiatry, Epidemiological and Social Psychiatric Research institute, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Hek
authors.affiliation: Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Lee
authors.affiliation: QIMR Berghofer Institute of Medical Research, Brisbane, QLD, Australia.|Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia.
authors.forename: E M
authors.initials: EM
authors.lastname: Byrne
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: S S
authors.initials: SS
authors.lastname: Mirza
authors.affiliation: Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: M G
authors.initials: MG
authors.lastname: Nivard
authors.affiliation: Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Bigdeli
authors.affiliation: Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Aggen
authors.affiliation: Department of Pharmacy, Center for Biomarker Research and Personalized Medicine, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Adkins
authors.affiliation: Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: A
authors.identifier: 0000-0003-2542-2202
authors.initials: A
authors.lastname: Wolen
authors.affiliation: Mental Health Service Line, Washington VA Medical Center, Washington DC, USA.|Department of Psychiatry, Georgetown University School of Medicine, Washington DC, USA.
authors.forename: A
authors.initials: A
authors.lastname: Fanous
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado, Boulder, CO, USA.|Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Keller
authors.affiliation: Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Castelao
authors.affiliation: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.|Institute of Social and Preventive Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.|Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Z
authors.identifier: 0000-0001-8285-7523
authors.initials: Z
authors.lastname: Kutalik
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Van der Auwera
authors.affiliation: Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst Moritz Arndt-University Greifswald, Greifswald, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Homuth
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Nauck
authors.affiliation: Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
authors.forename: A
authors.identifier: 0000-0002-8309-094X
authors.initials: A
authors.lastname: Teumer
authors.affiliation: Department of Psychiatry, VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands.|EMGO+ Institute for Health and Care Research, VU University Medical Centre, Amsterdam, The Netherlands.
authors.forename: Y
authors.initials: Y
authors.lastname: Milaneschi
authors.affiliation: Department of Psychiatry, VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands.|EMGO+ Institute for Health and Care Research, VU University Medical Centre, Amsterdam, The Netherlands.
authors.forename: J-J
authors.initials: JJ
authors.lastname: Hottenga
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: Direk
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.|Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Uitterlinden
authors.affiliation: Department of Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: C L
authors.initials: CL
authors.lastname: Mulder
authors.affiliation: QIMR Berghofer Institute of Medical Research, Brisbane, QLD, Australia.|Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia.
authors.forename: A K
authors.initials: AK
authors.lastname: Henders
authors.affiliation: QIMR Berghofer Institute of Medical Research, Brisbane, QLD, Australia.
authors.forename: S E
authors.initials: SE
authors.lastname: Medland
authors.affiliation: QIMR Berghofer Institute of Medical Research, Brisbane, QLD, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Gordon
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Heath
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: P A F
authors.initials: PA
authors.lastname: Madden
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.|Florida Atlantic University, Boca Raton, FL, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Pergadia
authors.affiliation: Department of Genetic Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: P J
authors.initials: PJ
authors.lastname: van der Most
authors.affiliation: Department of Genetic Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: I M
authors.initials: IM
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authors.affiliation: Department of Child and Adolescent Psychiatry/Psychology, Erasmus Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: F V A
authors.initials: FV
authors.lastname: van Oort
authors.affiliation: Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: C A
authors.initials: CA
authors.lastname: Hartman
authors.affiliation: Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: A J
authors.initials: AJ
authors.lastname: Oldehinkel
authors.affiliation: Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Preisig
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.|Department of Psychiatry and Psychotherapy, Helios Hospital Stralsund, Stralsund, Germany.
authors.forename: H J
authors.initials: HJ
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authors.affiliation: Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands.|Department of Child and Adolescent Psychiatry, GGZ inGeest/VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: C M
authors.initials: CM
authors.lastname: Middeldorp
authors.affiliation: Department of Psychiatry, VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands.|EMGO+ Institute for Health and Care Research, VU University Medical Centre, Amsterdam, The Netherlands.
authors.forename: B W J H
authors.initials: BW
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authors.affiliation: Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands.|EMGO+ Institute for Health and Care Research, VU University Medical Centre, Amsterdam, The Netherlands.
authors.forename: D
authors.initials: D
authors.lastname: Boomsma
authors.affiliation: QIMR Berghofer Institute of Medical Research, Brisbane, QLD, Australia.
authors.forename: N G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: QIMR Berghofer Institute of Medical Research, Brisbane, QLD, Australia.
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authors.affiliation: Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
authors.forename: B S
authors.initials: BS
authors.lastname: Maher
authors.affiliation: Department of Pharmacy, Center for Biomarker Research and Personalized Medicine, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: van den Oord
authors.affiliation: QIMR Berghofer Institute of Medical Research, Brisbane, QLD, Australia.|Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia.
authors.forename: N R
authors.initials: NR
authors.lastname: Wray
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.|Department of Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands.|Department of Child and Adolescent Psychiatry, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: H
authors.identifier: 0000-0002-4395-1397
authors.initials: H
authors.lastname: Tiemeier
authors.affiliation: Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
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mesh_terms: D001008:Anxiety Disorders / Q000235:genetics*; D016022:Case-Control Studies; D056726:Genetic Association Studies / Q000379:methods; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D044465:White People / Q000235:genetics