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

Sandra M. Meier; Kalevi Trontti; Kirstin L. Purves; Thomas Damm Als; Jakob Grove; Mikaela Laine; Marianne Giørtz Pedersen; Jonas Bybjerg-Grauholm; Marie Bækved-Hansen; Ewa Sokolowska; Preben B. Mortensen; David M. Hougaard; Thomas Werge; Merete Nordentoft; Gerome Breen; Anders D. Børglum; Thalia C. Eley; Iiris Hovatta; Manuel Mattheisen; Ole Mors

doi:10.1001/jamapsychiatry.2019.1119

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

Sandra M. Meier^*, Kalevi Trontti, Kirstin L. Purves, Thomas Damm Als, Jakob Grove, Mikaela Laine, Marianne Giørtz Pedersen, Jonas Bybjerg-Grauholm, Marie Bækved-Hansen, Ewa Sokolowska, Preben B. Mortensen, David M. Hougaard, Thomas Werge, Merete Nordentoft, Gerome Breen, Anders D. Børglum, Thalia C. Eley, Iiris Hovatta, Manuel Mattheisen, Ole Mors

^*Corresponding author for this work

Department of Clinical Medicine

25 Citations (Scopus)

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 12655 individuals with various anxiety and stress-related diagnoses and 19225 controls. Overall, 17740 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.

Original language	English
Journal	JAMA Psychiatry
ISSN	2168-622X
DOIs	https://doi.org/10.1001/jamapsychiatry.2019.1119
Publication status	Published - Sept 2019

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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. (2019). Genetic Variants Associated with Anxiety and Stress-Related Disorders: A Genome-Wide Association Study and Mouse-Model Study. JAMA Psychiatry. https://doi.org/10.1001/jamapsychiatry.2019.1119

Meier, SM, Trontti, K, Purves, KL, Als, TD, Grove, J, Laine, M, Pedersen, MG, Bybjerg-Grauholm, J, Bækved-Hansen, M, Sokolowska, E, Mortensen, PB, Hougaard, DM, Werge, T , Nordentoft, M, Breen, G, Børglum, AD, Eley, TC, Hovatta, I, Mattheisen, M & Mors, O 2019, 'Genetic Variants Associated with Anxiety and Stress-Related Disorders: A Genome-Wide Association Study and Mouse-Model Study', JAMA Psychiatry. https://doi.org/10.1001/jamapsychiatry.2019.1119

@article{5b5ce99d83a1494c8212513b6c799199,

title = "Genetic Variants Associated with Anxiety and Stress-Related Disorders: A Genome-Wide Association Study and Mouse-Model Study",

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 12655 individuals with various anxiety and stress-related diagnoses and 19225 controls. Overall, 17740 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.",

author = "Meier, {Sandra M.} and Kalevi Trontti and Purves, {Kirstin L.} and Als, {Thomas Damm} and Jakob Grove and Mikaela Laine and Pedersen, {Marianne Gi{\o}rtz} and Jonas Bybjerg-Grauholm and Marie B{\ae}kved-Hansen and Ewa Sokolowska and Mortensen, {Preben B.} and Hougaard, {David M.} and Thomas Werge and Merete Nordentoft and Gerome Breen and B{\o}rglum, {Anders D.} and Eley, {Thalia C.} and Iiris Hovatta and Manuel Mattheisen and Ole Mors",

year = "2019",

month = sep,

doi = "10.1001/jamapsychiatry.2019.1119",

language = "English",

journal = "JAMA Psychiatry",

issn = "2168-622X",

publisher = "The JAMA Network",

}

TY - JOUR

T1 - Genetic Variants Associated with Anxiety and Stress-Related Disorders

T2 - A Genome-Wide Association Study and Mouse-Model Study

AU - Meier, Sandra M.

AU - Trontti, Kalevi

AU - Purves, Kirstin L.

AU - Als, Thomas Damm

AU - Grove, Jakob

AU - Laine, Mikaela

AU - Pedersen, Marianne Giørtz

AU - Bybjerg-Grauholm, Jonas

AU - Bækved-Hansen, Marie

AU - Sokolowska, Ewa

AU - Mortensen, Preben B.

AU - Hougaard, David M.

AU - Werge, Thomas

AU - Nordentoft, Merete

AU - Breen, Gerome

AU - Børglum, Anders D.

AU - Eley, Thalia C.

AU - Hovatta, Iiris

AU - Mattheisen, Manuel

AU - Mors, Ole

PY - 2019/9

Y1 - 2019/9

N2 - 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 12655 individuals with various anxiety and stress-related diagnoses and 19225 controls. Overall, 17740 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.

AB - 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 12655 individuals with various anxiety and stress-related diagnoses and 19225 controls. Overall, 17740 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.

U2 - 10.1001/jamapsychiatry.2019.1119

DO - 10.1001/jamapsychiatry.2019.1119

M3 - Journal article

C2 - 31116379

AN - SCOPUS:85066912475

SN - 2168-622X

JO - JAMA Psychiatry

JF - JAMA Psychiatry

ER -

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

Abstract

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