title: Converging evidence for an impact of a functional NOS gene variation on anxiety-related processes.
abstract: Being a complex phenotype with substantial heritability, anxiety and related phenotypes are characterized by a complex polygenic basis. Thereby, one candidate pathway is neuronal nitric oxide (NO) signaling, and accordingly, rodent studies have identified NO synthase (NOS-I), encoded by NOS1, as a strong molecular candidate for modulating anxiety and hippocampus-dependent learning processes. Using a multi-dimensional and -methodological replication approach, we investigated the impact of a functional promoter polymorphism (NOS1-ex1f-VNTR) on human anxiety-related phenotypes in a total of 1019 healthy controls in five different studies. Homozygous carriers of the NOS1-ex1f short-allele displayed enhanced trait anxiety, worrying and depression scores. Furthermore, short-allele carriers were characterized by increased anxious apprehension during contextual fear conditioning. While autonomous measures (fear-potentiated startle) provided only suggestive evidence for a modulatory role of NOS1-ex1f-VNTR on (contextual) fear conditioning processes, neural activation at the amygdala/anterior hippocampus junction was significantly increased in short-allele carriers during context conditioning. Notably, this could not be attributed to morphological differences. In accordance with data from a plethora of rodent studies, we here provide converging evidence from behavioral, subjective, psychophysiological and neuroimaging studies in large human cohorts that NOS-I plays an important role in anxious apprehension but provide only limited evidence for a role in (contextual) fear conditioning.
authors.affiliation: Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, m.kuhn@uke.de.
authors.forename: Manuel
authors.initials: M
authors.lastname: Kuhn
authors.affiliation: Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Haaker
authors.affiliation: Department of Psychology I, Biological Psychology, Clinical Psychology, and Psychotherapy, University of Würzburg, Würzburg.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Glotzbach-Schoon
authors.affiliation: Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schümann
authors.affiliation: Department of Psychology I, Biological Psychology, Clinical Psychology, and Psychotherapy, University of Würzburg, Würzburg.
authors.forename: Marta
authors.initials: M
authors.lastname: Andreatta
authors.affiliation: Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: Mechias
authors.affiliation: Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Karolina
authors.initials: K
authors.lastname: Raczka
authors.affiliation: Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Gartmann
authors.affiliation: Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Büchel
authors.affiliation: Department of Psychology I, Biological Psychology, Clinical Psychology, and Psychotherapy, University of Würzburg, Würzburg, Department of Psychology, Clinical Psychology, and Psychotherapy, University of Regensburg, Regensburg.
authors.forename: Andreas
authors.initials: A
authors.lastname: Mühlberger
authors.affiliation: Department of Psychology I, Biological Psychology, Clinical Psychology, and Psychotherapy, University of Würzburg, Würzburg.
authors.forename: Paul
authors.initials: P
authors.lastname: Pauli
authors.affiliation: Department of Psychiatry, Psychosomatics, and Psychotherapy, University of Würzburg, Würzburg, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Johann Wolfgang Goethe-University, Frankfurt, and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Reif
authors.affiliation: Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, Neuroimaging Center (NIC), Focus Program Translational Neuroscience, Johannes Gutenberg University Medical Center Mainz, Germany.
authors.forename: Raffael
authors.initials: R
authors.lastname: Kalisch
authors.affiliation: Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Tina B
authors.initials: TB
authors.lastname: Lonsdorf
mesh_terms: D000328:Adult; D000679:Amygdala / Q000502:physiology*; D001007:Anxiety / Q000235:genetics*; D005239:Fear / Q000502:physiology*; D006624:Hippocampus / Q000502:physiology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D052248:Nitric Oxide Synthase Type I / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic
chemical_list: C496320:NOS1 protein, human; D052248:Nitric Oxide Synthase Type I
keywords: amygdala; anxiety; context conditioning; fMRI; hippocampus; nitric oxide synthase