An Association Analysis of Murine Anxiety Genes in Humans Implicates Novel Candidate Genes for Anxiety Disorders

Abstract

BackgroundHuman anxiety disorders are complex diseases with largely unknown etiology. We have taken a cross-species approach to identify genes that regulate anxiety-like behavior with inbred mouse strains that differ in their innate anxiety levels as a model. We previously identified 17 genes with expression levels that correlate with anxiety behavior across the studied strains. In the present study, we tested their 13 known human homologues as candidate genes for human anxiety disorders with a genetic association study.MethodsWe describe an anxiety disorder study sample derived from a Finnish population-based cohort and consisting of 321 patients and 653 carefully matched control subjects, all interviewed to obtain DSM-IV diagnoses. We genotyped altogether 208 single nucleotide polymorphisms (SNPs) (all non-synonymous SNPs, SNPs that alter potential microRNA binding sites, and gap-filling SNPs selected on the basis of HapMap information) from the investigated anxiety candidate genes.ResultsSpecific alleles and haplotypes of six of the examined genes revealed some evidence for association (p ≤ .01). The most significant evidence for association with different anxiety disorder subtypes were: p = .0009 with ALAD (δ-aminolevulinate dehydratase) in social phobia, p = .009 with DYNLL2 (dynein light chain 2) in generalized anxiety disorder, and p = .004 with PSAP (prosaposin) in panic disorder.ConclusionsOur findings suggest that variants in these genes might predispose to specific human anxiety disorders. These results illustrate the potential utility of cross-species approaches in identification of candidate genes for psychiatric disorders.

High-Resolution Genetic Mapping of Complex Traits from a Combined Analysis of F2 and Advanced Intercross Mice

“…Some of the genes within these regions had coding SNPs known to be involved in anxiety-like behavior and/or conditioned fear; examples include the nuclear receptor subfamily 6, group A, member 1 gene [Nr6a1 (Heydendael et al 2013)], the phospholipase D1 gene [Pld1 (Sun et al 2013)], the cadherin 23 gene [Cdh23 (Terracciano et al 2010, but see Schwander et al 2009)], the prosaposin gene [Psap (Hovatta et al 2005;Donner et al 2008)], and the SLIT and NTRK-like family, member 5 gene [Slitrk5 (Shmelkov et al 2010)]. However, we are cautious about interpreting the functional relevance of nonsynonymous coding SNPs; we do not currently have expression QTL (eQTL) data that could be used to detect heritable regulatory polymorphisms.…”

Controlling complexity: the clinical relevance of mouse complex genetics

“…Subsequently, they tested 13 known human homologs as candidate genes for human anxiety disorders and showed that several of them are associated with human anxiety disorders as well. 59 Malki et al 60 treated mice from different inbred strains with antidepressant drugs and measured gene expression levels in the hippocampus. Gene expression analysis of strain-by-drug interactions revealed 17 differentially expressed genes.…”

MicroRNA-Mediated Regulation and the Genetic Susceptibility to Anxiety Disorders

“…Using this kind of approach, a SNP in the 3'UTR of the aminolevulinate dehydratase (ALAD) was found to be associated with social phobia. Even though this is not a true poly-miRTS study, this association is of particular interest since the authors comment on the possibility that this SNP generates an illegitimate target site for miR-211 and miR-204 -as predicted by a miRNA target prediction program- (Donner et al, 2008). In this regard, an important bottle-neck in the study of poly-miRTS is the identification of miRNA target sites itself.…”