Genome-wide Association Study of Anxiety and Stress-related Disorders in the iPSYCH Cohort

Anxiety and stress-related disorders (ASRD) are among the most common mental disorders with the majority of patients suffering from additional disorders. Family and twin studies indicate that genetic and environmental factors are underlying their etiology. As ASRD are likely to configure various expressions of abnormalities in the basic stress-response system, we conducted a genome-wide association study including 12,655 cases with various anxiety and stress-related diagnoses and 19,225 controls. Standard association analyses were performed supplemented by a framework of sensitivity analyses. Variants in PDE4B showed consistent association with ASRD across a wide range of our analyses. In mice models, alternations in PDE4B expression were observed in those mice displaying anxious behavior after exposure to chronic stress. We also showed that 28% of the variance in ASRD was accounted for by common variants and that the genetic signature of ASRD overlapped with psychiatric traits, educational outcomes, obesity-related phenotypes, smoking, and reproductive success.

[1]  M. Daly,et al.  Genome-wide association study implicates CHRNA2 in cannabis use disorder , 2017, Nature Neuroscience.

[2]  Jakob Grove,et al.  Common risk variants identified in autism spectrum disorder , 2017, bioRxiv.

[3]  G. Breen,et al.  The Common Genetic Architecture of Anxiety Disorders , 2017, bioRxiv.

[4]  M. Daly,et al.  The iPSYCH2012 case–cohort sample: new directions for unravelling genetic and environmental architectures of severe mental disorders , 2017, Molecular Psychiatry.

[5]  R. Kessler,et al.  Genetic risk variants for social anxiety , 2017, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[6]  Dan J Stein,et al.  Largest GWAS of PTSD (N=20 070) yields genetic overlap with schizophrenia and sex differences in heritability , 2017, Molecular Psychiatry.

[7]  Kathleen F. Kerr,et al.  Genome‐wide association study of generalized anxiety symptoms in the Hispanic Community Health Study/Study of Latinos , 2017, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[8]  M. Gurney,et al.  Comparison of the Pharmacological Profiles of Selective PDE4B and PDE4D Inhibitors in the Central Nervous System , 2017, Scientific Reports.

[9]  N. Wray,et al.  Meta-analysis of genome-wide association studies of anxiety disorders , 2016, Molecular Psychiatry.

[10]  Naomi R. Wray,et al.  Common schizophrenia alleles are enriched in mutation-intolerant genes and maintained by background selection , 2016, bioRxiv.

[11]  R. Kessler,et al.  Genome-wide Association Studies of Posttraumatic Stress Disorder in 2 Cohorts of US Army Soldiers. , 2016, JAMA psychiatry.

[12]  Tom R. Gaunt,et al.  LD Hub: a centralized database and web interface to perform LD score regression that maximizes the potential of summary level GWAS data for SNP heritability and genetic correlation analysis , 2016, bioRxiv.

[13]  J. Smoller,et al.  Candidate genes in panic disorder: meta-analyses of 23 common variants in major anxiogenic pathways , 2016, Molecular Psychiatry.

[14]  K. Conneely,et al.  Genome-wide gene-based analysis suggests an association between Neuroligin 1 (NLGN1) and post-traumatic stress disorder , 2016, Translational psychiatry.

[15]  C. Spencer,et al.  A contribution of novel CNVs to schizophrenia from a genome-wide study of 41,321 subjects: CNV Analysis Group and the Schizophrenia Working Group of the Psychiatric Genomics Consortium , 2016, bioRxiv.

[16]  Leonardo Franklin Fontenelle,et al.  Aetiological overlap between obsessive–compulsive related and anxiety disorder symptoms: Multivariate twin study , 2016, British Journal of Psychiatry.

[17]  M. Hauser,et al.  Genome-wide association study of posttraumatic stress disorder in a cohort of Iraq-Afghanistan era veterans. , 2015, Journal of affective disorders.

[18]  Yakir A Reshef,et al.  Partitioning heritability by functional annotation using genome-wide association summary statistics , 2015, Nature Genetics.

[19]  Daniel E. Adkins,et al.  Meta-analysis of Genome-wide Association Studies for Neuroticism, and the Polygenic Association With Major Depressive Disorder. , 2015, JAMA psychiatry.

[20]  Jun S. Liu,et al.  The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans , 2015, Science.

[21]  M. Daly,et al.  An Atlas of Genetic Correlations across Human Diseases and Traits , 2015, Nature Genetics.

[22]  Joris M. Mooij,et al.  MAGMA: Generalized Gene-Set Analysis of GWAS Data , 2015, PLoS Comput. Biol..

[23]  Y. Torres,et al.  Anxious and non-anxious major depressive disorder in the World Health Organization World Mental Health Surveys , 2015, Epidemiology and Psychiatric Sciences.

[24]  C. Nievergelt,et al.  Genomic predictors of combat stress vulnerability and resilience in U.S. Marines: A genome-wide association study across multiple ancestries implicates PRTFDC1 as a potential PTSD gene , 2015, Psychoneuroendocrinology.

[25]  Matthew E. Ritchie,et al.  limma powers differential expression analyses for RNA-sequencing and microarray studies , 2015, Nucleic acids research.

[26]  C. Spencer,et al.  Biological Insights From 108 Schizophrenia-Associated Genetic Loci , 2014, Nature.

[27]  A. Bertelsen,et al.  A comprehensive nationwide study of the incidence rate and lifetime risk for treated mental disorders. , 2014, JAMA psychiatry.

[28]  M. Daly,et al.  LD Score regression distinguishes confounding from polygenicity in genome-wide association studies , 2014, Nature Genetics.

[29]  S. Galea,et al.  Genome-wide association study implicates a novel RNA gene, the lincRNA AC068718.1, as a risk factor for post-traumatic stress disorder in women , 2013, Psychoneuroendocrinology.

[30]  M. Glymour,et al.  Performance of Polygenic Scores for Predicting Phobic Anxiety , 2013, PloS one.

[31]  Hongyu Zhao,et al.  Genome-wide Association Study Identifies New Susceptibility Loci for Posttraumatic Stress Disorder , 2013, Biological Psychiatry.

[32]  M. Daly,et al.  Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis , 2013, The Lancet.

[33]  E. Shimizu,et al.  Meta-analysis of genome-wide association studies for panic disorder in the Japanese population , 2012, Translational Psychiatry.

[34]  R. Kessler,et al.  COMORBIDITY AND DISEASE BURDEN IN THE NATIONAL COMORBIDITY SURVEY REPLICATION (NCS‐R) , 2012, Depression and anxiety.

[35]  S. Galea,et al.  A genome-wide association study of posttraumatic stress disorder identifies the retinoid-related orphan receptor alpha (RORA) gene as a significant risk locus , 2012, Molecular Psychiatry.

[36]  R. Kessler,et al.  Prevalence, persistence, and sociodemographic correlates of DSM-IV disorders in the National Comorbidity Survey Replication Adolescent Supplement. , 2012, Archives of general psychiatry.

[37]  O. Delaneau,et al.  A linear complexity phasing method for thousands of genomes , 2011, Nature Methods.

[38]  J. Michopoulos,et al.  Anxiety disorders and obesity. , 2011, Psychiatrike = Psychiatriki.

[39]  J. Os,et al.  The size and burden of mental disorders and other disorders of the brain in Europe 2010 , 2011, European Neuropsychopharmacology.

[40]  S. Russo,et al.  A standardized protocol for repeated social defeat stress in mice , 2011, Nature Protocols.

[41]  F. J. V. van Steensel,et al.  Anxiety Disorders in Children and Adolescents with Autistic Spectrum Disorders: A Meta-Analysis , 2011, Clinical child and family psychology review.

[42]  S. Cichon,et al.  TMEM132D, a new candidate for anxiety phenotypes: evidence from human and mouse studies , 2011, Molecular Psychiatry.

[43]  K. Tokunaga,et al.  Association study of PDE4B with panic disorder in the Japanese population , 2011, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[44]  A. Zangen,et al.  Resilience to Chronic Stress Is Mediated by Hippocampal Brain-Derived Neurotrophic Factor , 2011, The Journal of Neuroscience.

[45]  D. Altshuler,et al.  A map of human genome variation from population-scale sequencing , 2010, Nature.

[46]  Yun Li,et al.  METAL: fast and efficient meta-analysis of genomewide association scans , 2010, Bioinform..

[47]  Marilyn C Cornelis,et al.  Genetics of Post-Traumatic Stress Disorder: Review and Recommendations for Genome-Wide Association Studies , 2010, Current psychiatry reports.

[48]  K. Tokunaga,et al.  Replication of a genome-wide association study of panic disorder in a Japanese population , 2010, Journal of Human Genetics.

[49]  P. Visscher,et al.  Common polygenic variation contributes to risk of schizophrenia and bipolar disorder , 2009, Nature.

[50]  P. Donnelly,et al.  A Flexible and Accurate Genotype Imputation Method for the Next Generation of Genome-Wide Association Studies , 2009, PLoS genetics.

[51]  D. Hougaard,et al.  High-throughput genotyping on archived dried blood spot samples. , 2009, Genetic testing and molecular biomarkers.

[52]  K. Tokunaga,et al.  Genome-wide association study of panic disorder in the Japanese population , 2009, Journal of Human Genetics.

[53]  J. O'Donnell,et al.  Anxiogenic-Like Behavioral Phenotype of Mice Deficient in Phosphodiesterase 4B (PDE4B) , 2008, Neuropsychopharmacology.

[54]  D. Hougaard,et al.  Storage policies and use of the Danish Newborn Screening Biobank , 2007, Journal of Inherited Metabolic Disease.

[55]  D. Reich,et al.  Principal components analysis corrects for stratification in genome-wide association studies , 2006, Nature Genetics.

[56]  Olga V. Demler,et al.  Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. , 2005, Archives of general psychiatry.

[57]  Michael C Neale,et al.  The structure of genetic and environmental risk factors for anxiety disorders in men and women. , 2005, Archives of general psychiatry.

[58]  M C Neale,et al.  A review and meta-analysis of the genetic epidemiology of anxiety disorders. , 2001, The American journal of psychiatry.

[59]  Thomas R. Gingeras,et al.  STAR: ultrafast universal RNA-seq aligner , 2013, Bioinform..

[60]  Cheng Li,et al.  Adjusting batch effects in microarray expression data using empirical Bayes methods. , 2007, Biostatistics.

[61]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .