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.
Highlights
With the advances in genome-wide screening arrays and sequencing technologies, scientists were enabled to examine genetic variations and their effect on behavioral phenotypes
Considering the mechanisms by which copy number variants (CNVs) might act on gene expression and their high abundance across the genome, their contribution is likely to be of importance [19]
The size range of CNVs detected by the two arrays was in a range to be expected. [23, 54,55,56,57,58] All CNVs taken together, their total size of about 97.3 Mb, 14.7 Mb (JaxMDGA) and 27.2 Mb (NGS) represent about 3.7%, 0.6% (JaxMDGA) and 1.0% (NGS) of the whole genome, respectively
Summary
With the advances in genome-wide screening arrays and sequencing technologies, scientists were enabled to examine genetic variations and their effect on behavioral phenotypes. In recent years a new type of variation became increasingly important: the copy number variants (CNVs). Have CNVs already been associated with common disorders and metabolic diseases like asthma, type 2 diabetes, obesity and cancer [1,2,3,4], they have been reported to affect disease susceptibility of neurological disorders including Parkinson’s disease, Alzheimer’s disease, autism, schizophrenia, bipolar disorders and anxiety disorders [5,6,7,8,9,10,11,12,13,14,15,16,17]. A large and common CNV in mice including the Glyoxalase 1 (Glo1) locus has been associated with anxiety-like behavior [18]. Considering the mechanisms by which CNVs might act on gene expression and their high abundance across the genome, their contribution is likely to be of importance [19]
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