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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.
