title: Connecting Anxiety and Genomic Copy Number Variation: A Genome-Wide Analysis in CD-1 Mice.
abstract: Genomic copy number variants (CNVs) have been implicated in multiple psychiatric disorders, but not much is known about their influence on anxiety disorders specifically. Using next-generation sequencing (NGS) and two additional array-based genotyping approaches, we detected CNVs in a mouse model consisting of two inbred mouse lines showing high (HAB) and low (LAB) anxiety-related behavior, respectively. An influence of CNVs on gene expression in the central (CeA) and basolateral (BLA) amygdala, paraventricular nucleus (PVN), and cingulate cortex (Cg) was shown by a two-proportion Z-test (p = 1.6 x 10-31), with a positive correlation in the CeA (p = 0.0062), PVN (p = 0.0046) and Cg (p = 0.0114), indicating a contribution of CNVs to the genetic predisposition to trait anxiety in the specific context of HAB/LAB mice. In order to confirm anxiety-relevant CNVs and corresponding genes in a second mouse model, we further examined CD-1 outbred mice. We revealed the distribution of CNVs by genotyping 64 CD 1 individuals using a high-density genotyping array (Jackson Laboratory). 78 genes within those CNVs were identified to show nominally significant association (48 genes), or a statistical trend in their association (30 genes) with the time animals spent on the open arms of the elevated plus-maze (EPM). Fifteen of them were considered promising candidate genes of anxiety-related behavior as we could show a significant overlap (permutation test, p = 0.0051) with genes within HAB/LAB CNVs. Thus, here we provide what is to our knowledge the first extensive catalogue of CNVs in CD-1 mice and potential corresponding candidate genes linked to anxiety-related behavior in mice.
authors.affiliation: Department of Behavioral Neuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Brenndörfer
authors.affiliation: Department of Statistical Genetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Altmann
authors.affiliation: Department of Behavioral Neuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Widner-Andrä
authors.affiliation: Department of Statistical Genetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Benno
authors.initials: B
authors.lastname: Pütz
authors.affiliation: Department of Statistical Genetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Darina
authors.initials: D
authors.lastname: Czamara
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Munich, Germany; Institute of Human Genetics, Technische Universität München, Munich, Germany.
authors.forename: Erik
authors.initials: E
authors.lastname: Tilch
authors.affiliation: Department of Statistical Genetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Tony
authors.initials: T
authors.lastname: Kam-Thong
authors.affiliation: Department of Molecular Genetics of Affective Disorders, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Weber
authors.affiliation: Department of Molecular Genetics of Affective Disorders, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Rex-Haffner
authors.affiliation: Department of Behavioral Neuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bettecken
authors.affiliation: Department of Behavioral Neuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bultmann
authors.affiliation: Department of Statistical Genetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Bertram
authors.initials: B
authors.lastname: Müller-Myhsok
authors.affiliation: Department of Molecular Genetics of Affective Disorders, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Elisabeth E
authors.initials: EE
authors.lastname: Binder
authors.affiliation: Department of Behavioral Neuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Landgraf
authors.affiliation: Department of Behavioral Neuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Czibere
mesh_terms: D000818:Animals; D001008:Anxiety Disorders / Q000235:genetics*; D066272:Basolateral Nuclear Complex / Q000378:metabolism; D066274:Central Amygdaloid Nucleus / Q000378:metabolism; D056915:DNA Copy Number Variations; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D060005:Genotyping Techniques / Q000379:methods*; D006179:Gyrus Cinguli / Q000378:metabolism; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D051379:Mice; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism; D017422:Sequence Analysis, DNA / Q000379:methods