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Anxiety GWAS, Mouse Model Experiments Lead to Potential New Drug Target

NEW YORK (GenomeWeb) – A team from Denmark, Germany, and elsewhere has identified new genetic contributors to anxiety and stress-related disorders, including variants in a proposed new drug target.

Using genotypes for nearly 32,000 Danish individuals with or without anxiety and stress-related disorders, in combination with national registry data on related diagnoses in Denmark, the researchers performed a genome-wide association study aimed at finding new risk variants, genes, and pathways for the psychiatric conditions, while estimating the SNP-based heritability of the conditions and exploring genetic features that overlap with those contributing to other neuropsychiatric disorders. Their results were reported online yesterday in JAMA Psychiatry.

Along with potential ties to other conditions, ranging from obesity to psychiatric disease, the team emphasized a strong association between anxiety and stress-related disorders and SNPs in PDE4B, a gene that codes for an intracellular cyclic adenosine monophosphate signaling regulator. That prompted speculation that PDE4B may serve as a target in future treatments for anxiety and stress-related conditions — a possibility that was subsequently investigated in inbred mice accustomed to "chronic social defeat," a model for human anxiety and stress disorders.

"We highlight the candidate gene PDE4B as a robust risk locus (through studies in mice and humans), pointing to a potential of PDE4B inhibitors in treatment of these disorders," first and corresponding author Sandra Meier and her co-authors wrote.

Meier is currently a researcher in the department of psychiatry at Dalhousie University. She previously held a postdoctoral position at Aarhus University and was affiliated with the University Hospital Würzburg.

They cautioned that additional research and replication will be required to "detect additional loci, not only identifying potential pleiotropic effects across the full spectrum of anxiety and stress-related disorders, but also loci associated specifically with individual disorders."

For their current study, the researchers focused on individuals participating in the Lundbeck Foundation's "Initiative for Integrative Psychiatric Research" (iPSYCH) study, comparing array-based genotypes in 12,655 Danish individuals with anxiety and stress-related diagnoses to 19,225 unaffected controls from the same population. The cohort included individuals born as early as 1981 and as recently as 2005.

The GWAS unearthed nearly six dozen variants on a chromosome 1 region containing PDE4B that had genome-wide significant ties to anxiety and stress-related disorders, the team reported, along with more nominal associations at sites in and around genes on several other chromosomes.

The researchers estimated the SNP-based heritability of anxiety and stress-related disorders and identified genetic correlation between anxiety and traits related to obesity, other psychiatric conditions, educational outcomes, and reproductive outcomes. From there, they focused in on PDE4B, uncovering that expression of the gene is dialed down in median prefrontal cortex and ventral hippocampus brain regions from chronically-stressed mice assessed by RNA sequencing.

"This study highlights anxiety and stress-related disorders as complex heritable phenotypes with intriguing genetic correlations not only with psychiatric traits, but also with educational outcomes and multiple obesity-related phenotypes," the authors wrote.

In a related editorial, University of Freiburg researchers Katharina Domschke and Michael Gottschalk called PDE4B "a promising new candidate gene … that crosses classic categorical disease boundaries."

Across anxiety and other complex psychiatric conditions, meanwhile, "ever-growing sizes of clinical and population samples are warranted to disentangle independent dimensional psychopathological factors of anxiety, trauma susceptibility, and depression associated with distinct polygenic risk signatures," they wrote.