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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.

Importance: Several mental disorders have consistently been found to be associated with decreased life expectancy, but little is known about whether this is also the case for obsessive-compulsive disorder (OCD)., Objective: To determine whether persons who receive a diagnosis of OCD are at increased risk of death., Design, Setting, and Participants: Using data from Danish registers, we conducted a nationwide prospective cohort study with 30 million person-years of follow-up. The data were collected from Danish longitudinal registers. A total of 3 million people born between 1955 and 2006 were followed up from January 1, 2002, through December 31, 2011. During this period, 27,236 people died. The data were analyzed primarily in June 2015., Main Outcomes and Measures: We estimated mortality rate ratios (MRRs), adjusted for calendar year, age, sex, maternal and paternal age, place of residence at birth, and somatic comorbidities, to compare persons with OCT with persons without OCD., Results: Of 10,155 persons with OCD (5935 women and 4220 men with a mean [SD] age of 29.1 [11.3] years who contributed a total of 54,937 person-years of observation), 110 (1.1%) died during the average follow-up of 9.7 years. The risk of death by natural or unnatural causes was significantly higher among persons with OCD (MRR, 1.68 [95% CI, 1.31-2.12] for natural causes; MRR, 2.61 [95% CI, 1.91-3.47] for unnatural causes) than among the general population. After the exclusion of persons with comorbid anxiety disorders, depression, or substance use disorders, OCD was still associated with increased mortality risk (MRR, 1.88 [95% CI, 1.27-2.67])., Conclusions and Relevance: The presence of OCD was associated with a significantly increased mortality risk. Comorbid anxiety disorders, depression, or substance use disorders further increased the risk. However, after adjusting for these and somatic comorbidities, we found that the mortality risk remained significantly increased among persons with OCD., Competing Interests: Disclosures: None reported.

Importance: Despite a remarkable co-occurrence of obsessive-compulsive disorder (OCD) and schizophrenia, little is known about the clinical and etiological relationship of these 2 disorders. Exploring the degree to which these disorders share etiological factors might provide useful implications for clinicians, researchers, and those with the disorders., Objectives: To assess whether patients with OCD experience an enhanced risk of developing schizophrenia and schizophrenia spectrum disorders and to determine whether a family history of OCD constitutes a risk factor for schizophrenia and schizophrenia spectrum disorders., Design, Setting, and Participants: Using individual data from longitudinal nationwide Danish registers, we conducted a prospective cohort study with 45 million person-years of follow-up. All survival analyses were adjusted for sex, age, calendar year, parental age, and place of residence at the time of birth. A total of 3 million people born between January 1, 1955, and November 30, 2006, were followed up from January 1, 1995, through December 31, 2012. During this period, 30 556 people developed schizophrenia or schizophrenia spectrum disorders., Main Outcomes and Measures: The presence of a prior diagnosis of OCD and the risk of a first lifetime diagnosis of schizophrenia and a schizophrenia spectrum disorder assigned by a psychiatrist in a hospital, outpatient clinic, or emergency department setting. Incidence rate ratios (IRRs) and accompanying 95% confidence intervals are used as measures of relative risk., Results: The presence of prior diagnosis of OCD was associated with an increased risk of developing schizophrenia (IRR = 6.90; 95% CI, 6.25-7.60) and schizophrenia spectrum disorders (IRR = 5.77; 95% CI, 5.33-6.22) later in life. Similarly, offspring of parents diagnosed as having OCD had an increased risk of schizophrenia (IRR = 4.31; 95% CI, 2.72-6.43) and schizophrenia spectrum disorders (IRR = 3.10; 95% CI, 2.17-4.27). The results remained significant after adjusting for family history of psychiatric disorders and the patient's psychiatric history., Conclusions and Relevance: A diagnosis of OCD was associated with higher rates of schizophrenia and schizophrenia spectrum disorders. The observed increase in risk suggests that OCD, schizophrenia, and schizophrenia spectrum disorders probably lay on a common etiological pathway.