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

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Research JAMA Psychiatry | Original Investigation Genetic Variants Associated With Anxiety and Stress-Related Disorders A Genome-Wide Association Study and Mouse-Model Study Sandra M. Meier, PhD; Kalevi Trontti, PhD; Kirstin L. Purves, MSc; Thomas Damm Als, PhD; Jakob Grove, PhD; Mikaela Laine, MSc; Marianne Giørtz Pedersen, MSc; Jonas Bybjerg-Grauholm, PhD; Marie Bækved-Hansen, PhD; Ewa Sokolowska, PhD; Preben B. Mortensen, DrMedSc; David M. Hougaard, DrMedSc; Thomas Werge, PhD; Merete Nordentoft, PhD; Gerome Breen, PhD; Anders D. Børglum, MD; Thalia C. Eley, PhD; Iiris Hovatta, PhD; Manuel Mattheisen, MD; Ole Mors, PhD Editorial page 889 IMPORTANCE Anxiety and stress-related disorders are among the most common mental Supplemental content 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 Author Affiliations: Author complex heritable phenotypes with intriguing genetic correlations not only with psychiatric affiliations are listed at the end of this article. traits, but also with educational outcomes and multiple obesity-related phenotypes. Corresponding Author: Sandra M. Furthermore, we highlight the candidate gene PDE4B as a robust risk locus pointing to Meier, PhD, Department of the potential of PDE4B inhibitors in treatment of these disorders. Psychiatry, Dalhousie University, 5850/5980 University Ave, PO Box JAMA Psychiatry. 2019;76(9):924-932. doi:10.1001/jamapsychiatry.2019.1119 9700, Halifax, NS B3K 6R8, Canada Published online May 22, 2019. ([email protected]). 924 (Reprinted) jamapsychiatry.com © 2019 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Genetic Variants Associated With Anxiety and Stress-Related Disorders Original Investigation Research nxiety disorders are characterized by excessive and inappropriate fear and anxiety triggered by stimuli per- Key Points ceived as threatening. They are among the most com- A Question Which genetic variants are associated with anxiety and mon mental disorders with a lifetime prevalence of more than stress-related disorders and do they correlate with other traits? 20%.1 Given the prevalence and the immense social and eco- Findings In this study of genome-wide association data, PDE4B nomic burden of these disorders,2 it is of strong interest to variants were associated with anxiety and stress-related disorders, identify their risk factors. and their genetic signature overlapped with other psychiatric Family and twin studies indicate that both genetic and en- traits, educational outcomes, obesity-related phenotypes, vironmental factors are of relevance in the etiology of anxiety smoking, and reproductive success. disorders, with levels of familial aggregation and heritability at Meaning Large samples are needed to validly identify genetic 30% to 50%.3 Although stress-related disorders share many variants associated with anxiety and stress-related disorders. symptom characteristics with anxiety disorders and both con- ditions are highly comorbid, they have recently been moved to a separate diagnostic category. Interestingly, susceptibility fac- Biobank.23 Following protocols for DNA extraction and am- tors common to different anxiety and stress-related disorders plification (described elsewhere24), all samples were geno- seem to account for a larger proportion in heritability than fac- typed using Illumina’s PsychChip (Illumina). Through the na- tors predisposing to individual disorders.4 This indicates the tional research registers,25,26 we identified individuals with potential of combining these phenotypes to identify their shared an anxiety and stress-related diagnosis assigned by a psychia- genetic underpinnings. Genome-wide association studies trist during routine clinical care according to the Interna- (GWAS) have proven to be an effective tool for the identifica- tional Statistical Classification of Diseases and Related Health tion of common genetic variants increasing the susceptibility Problems, Tenth Revision (F40.0-F41.9; F43.0-F43.9). Indi- to complex disorders. Recently,GWAS of panic disorder,5-8 post- viduals with comorbid autism were excluded. Although pa- traumatic stress disorder,9-15 generalized anxiety disorders,16 tients with autism experience anxiety, their anxiety is often phobias,17,18 and a composite indicator of anxiety disorders19,20 reflecting their core autistic symptomatology and lacks the have been published. However, besides the study by Purves social component central to many anxiety and stress-related et al,20 most of these efforts were limited in sample size result- diagnoses.27 Exclusion criteria for control individuals were ing in low overall power to detect significant associations. International Statistical Classification of Diseases and Related In this study, we conducted a GWAS aggregating indivi- Health Problems, Tenth Revision diagnoses of anxiety, stress- duals in the Lundbeck Foundation Initiative for Integrative related disorders, and mood disorders. Characteristics of the Psychiatric Research (iPSYCH) study with varying diagnoses of sample are displayed in Table 1. The study was conducted anxiety and stress-related disorders to identify their common between June 2016 and November 2018. This study was ap- genetic factors, extending previous successful attempts.19,20 As proved by the Danish Data Protection Agency. By Danish law, most individuals with these disorders experience another co- registry-based studies do not require informed consent. morbid mental disorder, especially depression,21 we explored the association of mental comorbidity with the genetics of anxi- Quality Control, GWAS, and Gene-Based Analysis ety and stress-related disorders. Genes identified through this Quality control, imputation, and primary association analy- effort were further followed up in a mouse model of chronic so- ses in iPSYCH have been described elsewhere.28 We used the cial defeat. Our effort represents the first genetic study of this bioinformatics pipeline Ricopili29 developed by the Psychiat- magnitude to explicitly target comorbidity of anxiety and stress- ric Genomics Consortium.30 To avoid potential study effects related disorders, to our knowledge. of the 23 genotyping batches within the iPSYCH cohort, each batch was processed separately. Standard procedures for stringent quality control included filters for call rate, Hardy- Methods Weinberg equilibrium, and heterozygosity rates. Each batch was phased and imputed using the 1000 Genomes Project Participants phase 3 imputation reference panel31 using SHAPEIT32 and The GWAS sample under analysis included 12 655 individuals IMPUTE2,33 respectively. Cryptic relatedness and population with anxiety and stress-related diagnoses as well as 19 225 structure were assessed on high-quality single-nucleotide poly- controls from Denmark. All study participants were enrolled morphisms (SNPs) with low linkage disequilibrium (LD). in iPSYCH, a study designed to unravel risk factors of severe Genome-wide association studies for the 23 batches in mental
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