Genetic Variants Associated With Anxiety and Stress-Related Disorders: A Genome-Wide Association Study and Mouse-Model Study
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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 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 association of psychiatric comorbidities with genetic findings. Design, Setting, Participants: This genome-wide association study included individuals with various anxiety and stress-related diagnoses and controls derived from the population-based Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) study. Lifetime diagnoses of anxiety and stress-related disorders were obtained through the national Danish registers. Genes of interest were further evaluated in mice exposed to chronic social defeat. The study was conducted between June 2016 and November 2018. Main Outcomes and Measures: Diagnoses of a relatively broad diagnostic spectrum of anxiety and stress-related disorders. Results: The study sample included 12 655 individuals with various anxiety and stress-related diagnoses and 19 225 controls. Overall, 17 740 study participants (55.6%) were women. A total of 7308 participants (22.9%) were born between 1981-1985, 8840 (27.7%) between 1986-1990, 8157 (25.6%) between 1991-1995, 5918 (18.6%) between 1996-2000, and 1657 (5.2%) 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; odds ratio = 0.89; 95% CI, 0.86-0.92). 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 = .002; t = -3.33) and the hippocampus (P = .001; t = -3.72). We also found a single-nucleotide polymorphism heritability of 28% (standard error = 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: 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. Furthermore, we highlight the candidate gene PDE4B as a robust risk locus pointing to the potential of PDE4B inhibitors in treatment of these disorders.
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Genetic factors, the personality of the individual, and stressful life events could cause anxiety.
“In terms of the causes of anxiety both genetic (Meier et al., 2019), the personality of the individual (Prince et al., 2021) as well as stressful life events could cause anxiety (Miloyan et al., 2018).”
From A Systematic Review of “Helicopter Parenting” and Its Relationship With Anxiety and Depression (2022) · cites this paper as Meier et al., 2019
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“In terms of the causes of anxiety both genetic (Meier et al., 2019), the personality of the individual (Prince et al., 2021) as well as stressful life events could cause anxiety (Miloyan et al., 2018).”
Background
- Authors
- Meier, S. M., Trontti, K., Purves, K. L., Als, T. D., Grove, J., Laine, M., Pedersen, M. G., Bybjerg-Grauholm, J., Bækved-Hansen, M., Sokolowska, E., Mortensen, P. B., Hougaard, D. M., Werge, T., Nordentoft, M., Breen, G., Børglum, A. D., Eley, T. C., Hovatta, I., Mattheisen, M., & Mors, O.
- Affiliations
- Dalhousie University (CA)
- University of Helsinki (FI)
- King's College London (GB)
- Aarhus University (DK)
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Copenhagen, Denmark
- Statens Serum Institut (DK)
- University of Copenhagen (DK)
- National Health Service (GB)
- Aarhus University Hospital (DK)
- Corresponding author
- Meier, Sandra M.
- ORCID
- Venue
- JAMA Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2019-09-01
- Volume
- 76
- Issue
- 9
- Pages
- 924
- ISSN
- 2168-622X (ISSN-L)
- PMC
- PMC6537792
- OpenAlex
- W2946441043
- Cited by
- 240
- References
- 18
- Citations by year
- 2026: 16 · 2025: 38 · 2024: 40 · 2023: 33 · 2022: 55 · 2021: 35 · 2020: 15 · 2019: 8
- FWCI
- 17.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Psychiatry (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- Research Portal (King's College London) (submittedVersion)
- Funders
- Alexander von Humboldt-Stiftung
- King's College London
- Lundbeckfonden (R208-2015-3951, R155-2014-1724, R248‐2017‐2003)
- Sigrid Juséliuksen Säätiö
- Medical Research Council (MR/M021475/1, 1668713)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Keywords
- anxiety disorders, stress-related disorders, genetic risk variants, single nucleotide polymorphisms, heritability, PDE4B, chronic social defeat, chronic stress, prefrontal cortex, psychiatric comorbidity, pleiotropy, neuroinflammation, neuroendocrine stress response
- MeSH terms
- Trauma and Stressor Related Disorders, Social Defeat, Adolescent, Adult, Animals, Anxiety Disorders, Behavior, Animal, Denmark, Disease Models, Animal, Female, Hippocampus, Humans, Male, Mice, Inbred C57BL, Mice, Inbred DBA, Registries, Comorbidity, Prefrontal Cortex, Polymorphism, Single Nucleotide, Gene Expression Profiling, Mice, Cyclic Nucleotide Phosphodiesterases, Type 4, Genome-Wide Association Study, Young Adult
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