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Original Investigation
May 22, 2019

Genetic Variants Associated With Anxiety and Stress-Related Disorders: A Genome-Wide Association Study and Mouse-Model Study

Author Affiliations
  • 1Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark
  • 2The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Copenhagen, Denmark
  • 3Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital Würzburg, Würzburg, Germany
  • 4now with the Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada
  • 5Research Program of Molecular and Integrative Biosciences, Faculty of Biological and Environmental Sciences, Department of Psychology and Logopedics, Medicum, and SleepWell Research Program, University of Helsinki, Helsinki, Finland
  • 6Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom
  • 7Department of Biomedicine, Aarhus University, Aarhus, Denmark
  • 8Centre for integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark
  • 9National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark
  • 10Danish Centre for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
  • 11Institute of Biological Psychiatry, Mental Health Centre Sct Hans, Copenhagen University Hospital, Roskilde, Denmark
  • 12Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
  • 13Mental Health Centre Copenhagen, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
  • 14National Institute for Health Research Biomedical Research Centre for Mental Health, South London and Maudsley National Health Service Trust, London, United Kingdom
  • 15Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden
JAMA Psychiatry. 2019;76(9):924-932. doi:10.1001/jamapsychiatry.2019.1119
Key Points

Question  Which genetic variants are associated with anxiety and stress-related disorders and do they correlate with other traits?

Findings  In this study of genome-wide association data, PDE4B variants were associated with anxiety and stress-related disorders, and their genetic signature overlapped with other psychiatric traits, educational outcomes, obesity-related phenotypes, smoking, and reproductive success.

Meaning  Large samples are needed to validly identify genetic variants associated with anxiety and stress-related disorders.

Abstract

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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