Importance: Anxiety and stress-related disorders are among the most common mental disorders. Although, family and twin studies indicate that both genetic and environmental factors play an important role underlying their etiology; the genetic underpinnings of anxiety and stress-related disorders are only poorly understood.
Objectives: To estimate the single-nucleotide polymorphism-based heritability of anxiety and stress-related disorders; to identify novel genetic risk variants, genes, or biological pathways; to test for pleiotropic associations with other psychiatric traits; and to evaluate the impact of psychiatric comorbidities on genetic findings.
Design, Setting, Participants: We conducted a genome-wide association study including 12655 cases with various anxiety and stress-related diagnoses and 19225 controls derived from the population-based Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) study. The study was conducted between 2016 and 2018.
Main Outcomes and Measures: The study adopted relatively broad diagnostic spectrum of anxiety and stress-related disorders to maximize the sample size. Lifetime diagnoses of anxiety and stress-related disorders were obtained through the national Danish registers.
Results: The study sample included 12655 cases with various anxiety and stress-related diagnoses and 19225 controls, 17741 were women and 14139 men. 7308 of these study participants were born between 1981-1985, 8840 between 1986-1990, 8158 between 1991-1995, 5917 between 1996-200, and 1657 between 2001-2005. Standard association analysis revealed variants in PDE4B to be associated with anxiety and stress-related disorder (rs7528604, P=5.39*10-11, OR=0.89). A framework of sensitivity analyses adjusting for mental comorbidity supported this result showing consistent association of PDE4B variants with anxiety and stress-related disorder across analytical scenarios. In mouse models, alterations in Pde4b expression were observed in those mice displaying anxiety-like behavior after exposure to chronic stress in the prefrontal cortex (P=0.002) and the hippocampus (P=0.001). We also found a SNP heritability of 28% (SE=0.027) and that the genetic signature of anxiety and stress-related overlapped with psychiatric traits, educational outcomes, obesity-related phenotypes, smoking, and reproductive success.
Conclusions and Relevance: Our 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. Furthermore, we highlight the candidate gene PDE4B as a robust risk locus pointing to the potential of PDE4B inhibitors in treatment of these disorders.
- Psychiatric genetics
- Statistical genetics