Anxiety, Stress-Related Disorders Associated With Genetic Variants

Anxiety and stress-related phenotypes correlated with such traits as depression and obesity and smoking.

Anxiety and stress-related disorders are heritable phenotypes that correlate with psychiatric traits as well as obesity-related phenotypes and smoking, according to results from a genome-wide association study (GWAS) published in JAMA Psychiatry.

The present GWAS sample comprised 12,655 individuals with anxiety and stress-related disorders and 19,225 control individuals, all of whom were from Denmark and were enrolled in the population-based Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) study. iPSYCH researchers genotyped participant DNA using samples obtained at the Danish Neonatal Screening Biobank; for the present analyses, investigators conducted GWAS for the iPSYCH genotyping batches, using logistic regression models. As outcome measures, lifetime diagnoses of anxiety and stress-related disorders were obtained from Danish population registers. In addition, investigators performed a mouse-model study in which mice were exposed to chronic social defeat and then tested for social aversion. Linkage disequilibrium-score regression was used to calculate single nucleotide polymorphism (SNP) heritability of anxiety and stress-related disorders.

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In the total GWAS sample, 22.9% were born between 1981 and 1985, 27.7% between 1986 and 1990, 25.6% between 1991 and 1995, 18.6% between 1996 and 2000, and 5.2% between 2001 and 2005. A total of 17,740 participants (55.6%) were women.

“At a single locus on chromosome 1, 68 genetic variants exceeded the threshold for genome-wide significance in this GWAS for anxiety and stress-related disorders,” the investigators noted. “The locus [overlaps] with 1 gene (PDE4B) with the lead SNP rs7528604.” Per standard association analysis, variants in PDE4B were associated with anxiety and stress-related disorders (odds ratio, 0.89; 95% CI, 0.86-0.92; P =.539×10−10). In sensitivity analyses adjusted for mental comorbidity, associations between PDE4B variants and anxiety and stress-related disorders remained significant. In mouse models, alterations in Pde4b expression were observed the prefrontal cortex (P =.002) and hippocampus (P =.001) of mice displaying anxiety-like behavior after exposure to chronic stress.

Single-nucleotide polymorphism heritability was calculated at 0.28 (standard error, 0.027), assuming a prevalence of 20% for anxiety and stress-related disorders. In addition, 31 phenotypes displayed significant genetic correlation with anxiety and stress-related disorders (P =.219×10−3), including depression, neuroticism, obesity-related phenotypes, smoking, and reproductive success.

Per these data, anxiety and stress-related disorders were described as a “complex heritable phenotype,” with candidate gene PDE4B a potential target for intervention and further research. Future studies are necessary to confirm these findings and detect additional loci for anxiety and related disorders.


Meier SM, Trontti K, Purves KL, et al. Genetic variants associated with anxiety and stress-related disorders: a genome-wide association study and mouse-model study [published online May 22, 2019]. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2019.1119