Daniel F Levey1, Joel Gelernter1, Renato Polimanti1, Hang Zhou1, Zhongshan Cheng1, Mihaela Aslan1, Rachel Quaden1, John Concato1, Krishnan Radhakrishnan1, Julien Bryois1, Patrick F Sullivan1, Murray B Stein1. 1. Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, Conn., and Department of Psychiatry, Veterans Affairs Connecticut Healthcare Center, West Haven, Conn. (Levey, Gelernter, Polimanti, Zhou, Cheng); VA Clinical Epidemiology Research Center, VA Connecticut Healthcare System, West Haven, Conn. (Aslan, Concato, Radhakrishnan); Department of Medicine, Yale University School of Medicine, New Haven, Conn. (Aslan, Concato); Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston (Quaden); College of Medicine, University of Kentucky, Lexington (Radhakrishnan); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm (Bryois, Sullivan); Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill (Sullivan); Psychiatry Service, VA San Diego Healthcare System, San Diego, and Departments of Psychiatry and of Family Medicine and Public Health, University of California San Diego, La Jolla (Stein).
Abstract
OBJECTIVE: Anxiety disorders are common and often disabling. The goal of this study was to examine the genetic architecture of anxiety disorders and anxiety symptoms, which are also frequently comorbid with other mental disorders, such as major depressive disorder. METHODS: Using one of the world's largest biobanks including genetic, environmental, and medical information, the Million Veteran Program, the authors performed a genome-wide association study (GWAS) of a continuous trait for anxiety (based on score on the Generalized Anxiety Disorder 2-item scale [GAD-2], N=199,611) as the primary analysis and self-report of physician diagnosis of anxiety disorder (N=224,330) as a secondary analysis. RESULTS: The authors identified five genome-wide significant signals for European Americans and one for African Americans on GAD-2 score. The strongest were on chromosome 3 (rs4603973) near SATB1, a global regulator of gene expression, and on chromosome 6 (rs6557168) near ESR1, which encodes an estrogen receptor. The locus identified on chromosome 7 (rs56226325, MAF=0.17) near MAD1L1 was previously identified in GWASs of bipolar disorder and schizophrenia. The authors replicated these findings in the summary statistics of two major published GWASs for anxiety, and also found evidence of significant genetic correlation between the GAD-2 score results and previous GWASs for anxiety (rg=0.75), depression (rg=0.81), and neuroticism (rg=0.75). CONCLUSIONS: This is the largest GWAS of anxiety traits to date. The authors identified novel genome-wide significant associations near genes involved with global regulation of gene expression (SATB1) and the estrogen receptor alpha (ESR1). Additionally, the authors identified a locus (MAD1L1) that may have implications for genetic vulnerability across several psychiatric disorders. This work provides new insights into genetic risk mechanisms underpinning anxiety and related psychiatric disorders.
OBJECTIVE:Anxiety disorders are common and often disabling. The goal of this study was to examine the genetic architecture of anxiety disorders and anxiety symptoms, which are also frequently comorbid with other mental disorders, such as major depressive disorder. METHODS: Using one of the world's largest biobanks including genetic, environmental, and medical information, the Million Veteran Program, the authors performed a genome-wide association study (GWAS) of a continuous trait for anxiety (based on score on the Generalized Anxiety Disorder 2-item scale [GAD-2], N=199,611) as the primary analysis and self-report of physician diagnosis of anxiety disorder (N=224,330) as a secondary analysis. RESULTS: The authors identified five genome-wide significant signals for European Americans and one for African Americans on GAD-2 score. The strongest were on chromosome 3 (rs4603973) near SATB1, a global regulator of gene expression, and on chromosome 6 (rs6557168) near ESR1, which encodes an estrogen receptor. The locus identified on chromosome 7 (rs56226325, MAF=0.17) near MAD1L1 was previously identified in GWASs of bipolar disorder and schizophrenia. The authors replicated these findings in the summary statistics of two major published GWASs for anxiety, and also found evidence of significant genetic correlation between the GAD-2 score results and previous GWASs for anxiety (rg=0.75), depression (rg=0.81), and neuroticism (rg=0.75). CONCLUSIONS: This is the largest GWAS of anxiety traits to date. The authors identified novel genome-wide significant associations near genes involved with global regulation of gene expression (SATB1) and the estrogen receptor alpha (ESR1). Additionally, the authors identified a locus (MAD1L1) that may have implications for genetic vulnerability across several psychiatric disorders. This work provides new insights into genetic risk mechanisms underpinning anxiety and related psychiatric disorders.
Entities:
Keywords:
Anxiety Disorders; Anxiety Symptoms; Genome-Wide Association Study; Million Veteran Program; Psychiatric Comorbidity; Veterans
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