Connecting Anxiety and Genomic Copy Number Variation: A Genome-Wide Analysis in CD-1 Mice

PLoS One. 2015 May 26;10(5):e0128465. doi: 10.1371/journal.pone.0128465. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety Disorders / genetics*
  • Basolateral Nuclear Complex / metabolism
  • Central Amygdaloid Nucleus / metabolism
  • DNA Copy Number Variations*
  • Disease Models, Animal
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study / methods*
  • Genotyping Techniques / methods*
  • Gyrus Cinguli / metabolism
  • High-Throughput Nucleotide Sequencing / methods
  • Mice
  • Paraventricular Hypothalamic Nucleus / metabolism
  • Sequence Analysis, DNA / methods

Grants and funding

This study was funded by the Max Planck Institute of Psychiatry. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.