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Genome-wide association study of shared liability to anxiety disorders in Army STARRS.

ABSTRACT: Anxiety disorders (ANX), namely generalized anxiety, panic disorder, and phobias, are common, etiologically complex syndromes that show increasing prevalence and comorbidity throughout adolescence and beyond. Few genome-wide association studies (GWAS) examining ANX risk have been published and almost exclusively in individuals of European ancestry. In this study, we phenotyped participants from the Army Study To Assess Risk and Resilience in Servicemembers (STARRS) to approximate DSM-based ANX diagnoses. We factor-analyzed those to create a single dimensional anxiety score for each subject. GWAS were conducted using that score within each of three ancestral groups (EUR, AFR, LAT) and then meta-analyzed across ancestries (N_Total = 16,510). We sought to (a) replicate prior ANX GWAS findings in ANGST; (b) determine whether results extended to other ancestry groups; and (c) meta-analyze with ANGST for increased power to identify novel susceptibility loci. No reliable genome-wide significant SNP associations were detected in STARRS. However, SNPs within the CAMKMT gene located in region 2p21 associated with shared ANX risk in ANGST were replicated in EUR soldiers but not other ancestry groups. Combining EUR STARRS and ANGST (N = 28,950) yielded a more robust 2p21 association signal (p = 9.08x10^-11 ). Gene-based analyses supported three genes within 2p21 and LBX1 on chromosome 10. More powerful ANX genetic studies will be required to identify further loci.

SUBMITTER: Hettema JM

PROVIDER: S-EPMC7210051 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Genome-wide association study of shared liability to anxiety disorders in Army STARRS.

Hettema John M JM Verhulst Brad B Chatzinakos Chris C Bacanu Silviu-Alin SA Chen Chia-Yen CY Ursano Robert J RJ Kessler Ronald C RC Gelernter Joel J Smoller Jordan W JW He Feng F Jain Sonia S Stein Murray B MB

American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 20191230 4

Anxiety disorders (ANX), namely generalized anxiety, panic disorder, and phobias, are common, etiologically complex syndromes that show increasing prevalence and comorbidity throughout adolescence and beyond. Few genome-wide association studies (GWAS) examining ANX risk have been published and almost exclusively in individuals of European ancestry. In this study, we phenotyped participants from the Army Study To Assess Risk and Resilience in Servicemembers (STARRS) to approximate DSM-based ANX d ...[more]

PMID: 31886626

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Project description:ImportanceThe Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) is a multicomponent study designed to generate actionable recommendations to reduce Army suicides and increase knowledge of risk and resilience factors for suicidality.ObjectivesTo present data on prevalence, trends, and basic sociodemographic and Army experience correlates of suicides and accident deaths among active duty Regular Army soldiers between January 1, 2004, and December 31, 2009, and thereby establish a foundation for future Army STARRS investigations.Design, setting, and participantsAnalysis of trends and predictors of suicide and accident deaths using Army and Department of Defense administrative data systems. Participants were all members of the US Regular Army serving at any time between 2004 and 2009.Main outcomes and measuresDeath by suicide or accident during active Army service.ResultsThe suicide rate rose between 2004 and 2009 among never deployed and currently and previously deployed Regular Army soldiers. The accident death rate fell sharply among currently deployed soldiers, remained constant among the previously deployed, and trended upward among the never deployed. Increased suicide risk was associated with being a man (or a woman during deployment), white race/ethnicity, junior enlisted rank, recent demotion, and current or previous deployment. Sociodemographic and Army experience predictors were generally similar for suicides and accident deaths. Time trends in these predictors and in the Army's increased use of accession waivers (which relaxed some qualifications for new soldiers) do not explain the rise in Army suicides.Conclusions and relevancePredictors of Army suicides were largely similar to those reported elsewhere for civilians, although some predictors distinct to Army service emerged that deserve more in-depth analysis. The existence of a time trend in suicide risk among never-deployed soldiers argues indirectly against the view that exposure to combat-related trauma is the exclusive cause of the increase in Army suicides.

Project description:Tinnitus, a phantom perception of sound in the absence of any external sound source, is a prevalent health condition often accompanied by psychiatric comorbidities. Recent genome-wide association studies (GWAS) highlighted a polygenic nature of tinnitus susceptibility. A shared genetic component between tinnitus and psychiatric conditions remains elusive. Here we present a GWAS using the UK Biobank to investigate the genetic processes linked to tinnitus and tinnitus-related distress, followed by gene-set enrichment analyses. The UK Biobank sample comprised 132,438 individuals with tinnitus and genotype data. Among the study sample, 38,525 individuals reported tinnitus, and 26,889 participants mentioned they experienced tinnitus-related distress in daily living. The genome-wide association analyses were conducted on tinnitus and tinnitus-related distress. We conducted enrichment analyses using FUMA to further understand the genetic processes linked to tinnitus and tinnitus-related distress. A genome-wide significant locus (lead SNP: rs71595470) for tinnitus was obtained in the vicinity of GPM6A. Nineteen independent loci reached suggestive association with tinnitus. Fifteen independent loci reached suggestive association with tinnitus-related distress. The enrichment analysis revealed a shared genetic component between tinnitus and psychiatric traits, such as bipolar disorder, feeling worried, cognitive ability, fast beta electroencephalogram, and sensation seeking. Metabolic, cardiovascular, hematological, and pharmacological gene sets revealed a significant association with tinnitus. Anxiety and stress-related gene sets revealed a significant association with tinnitus-related distress. The GWAS signals for tinnitus were enriched in the hippocampus and cortex, and for tinnitus-related distress were enriched in the brain and spinal cord. This study provides novel insights into genetic processes associated with tinnitus and tinnitus-related distress and demonstrates a shared genetic component underlying tinnitus and psychiatric conditions. Further collaborative attempts are necessary to identify genetic components underlying the phenotypic heterogeneity in tinnitus and provide biological insight into the etiology.

Project description:ImportancePeople with major psychiatric disorders (MPDs) have a 10- to 20-year shorter life span than the rest of the population, and this difference is mainly due to comorbid cardiovascular diseases. Genome-wide association studies have identified common variants involved in schizophrenia (SCZ), bipolar disorder (BIP), and major depression (MD) and body mass index (BMI), a key cardiometabolic risk factor. However, genetic variants jointly influencing MPD and BMI remain largely unknown.ObjectiveTo assess the extent of the overlap between the genetic architectures of MPDs and BMI and identify genetic loci shared between them.Design, setting, and participantsUsing a conditional false discovery rate statistical framework, independent genome-wide association study data on individuals with SCZ (n = 82 315), BIP (n = 51 710), MD (n = 480 359), and BMI (n = 795 640) were analyzed. The UK Biobank cohort (n = 29 740) was excluded from the MD data set to avoid sample overlap. Data were collected from August 2017 to May 2018, and analysis began July 2018.Main outcomes and measuresThe primary outcomes were a list of genetic loci shared between BMI and MPDs and their functional pathways.ResultsGenome-wide association study data from 1 380 284 participants were analyzed, and the genetic correlation between BMI and MPDs varied (SCZ: r for genetic = -0.11, P = 2.1 × 10-10; BIP: r for genetic = -0.06, P = .0103; MD: r for genetic = 0.12, P = 6.7 × 10-10). Overall, 63, 17, and 32 loci shared between BMI and SCZ, BIP, and MD, respectively, were analyzed at conjunctional false discovery rate less than 0.01. Of the shared loci, 34% (73 of 213) in SCZ, 52% (36 of 69) in BIP, and 57% (56 of 99) in MD had risk alleles associated with higher BMI (conjunctional false discovery rate <0.05), while the rest had opposite directions of associations. Functional analyses indicated that the overlapping loci are involved in several pathways including neurodevelopment, neurotransmitter signaling, and intracellular processes, and the loci with concordant and opposite association directions pointed mostly to different pathways.Conclusions and relevanceIn this genome-wide association study, extensive polygenic overlap between BMI and SCZ, BIP, and MD were found, and 111 shared genetic loci were identified, implicating novel functional mechanisms. There was mixture of association directions in SCZ and BMI, albeit with a preponderance of discordant ones.

Project description:ImportanceThe US Army experienced a sharp increase in soldier suicides beginning in 2004. Administrative data reveal that among those at highest risk are soldiers in the 12 months after inpatient treatment of a psychiatric disorder.ObjectiveTo develop an actuarial risk algorithm predicting suicide in the 12 months after US Army soldier inpatient treatment of a psychiatric disorder to target expanded posthospitalization care.Design, setting, and participantsThere were 53,769 hospitalizations of active duty soldiers from January 1, 2004, through December 31, 2009, with International Classification of Diseases, Ninth Revision, Clinical Modification psychiatric admission diagnoses. Administrative data available before hospital discharge abstracted from a wide range of data systems (sociodemographic, US Army career, criminal justice, and medical or pharmacy) were used to predict suicides in the subsequent 12 months using machine learning methods (regression trees and penalized regressions) designed to evaluate cross-validated linear, nonlinear, and interactive predictive associations.Main outcomes and measuresSuicides of soldiers hospitalized with psychiatric disorders in the 12 months after hospital discharge.ResultsSixty-eight soldiers died by suicide within 12 months of hospital discharge (12.0% of all US Army suicides), equivalent to 263.9 suicides per 100,000 person-years compared with 18.5 suicides per 100,000 person-years in the total US Army. The strongest predictors included sociodemographics (male sex [odds ratio (OR), 7.9; 95% CI, 1.9-32.6] and late age of enlistment [OR, 1.9; 95% CI, 1.0-3.5]), criminal offenses (verbal violence [OR, 2.2; 95% CI, 1.2-4.0] and weapons possession [OR, 5.6; 95% CI, 1.7-18.3]), prior suicidality [OR, 2.9; 95% CI, 1.7-4.9], aspects of prior psychiatric inpatient and outpatient treatment (eg, number of antidepressant prescriptions filled in the past 12 months [OR, 1.3; 95% CI, 1.1-1.7]), and disorders diagnosed during the focal hospitalizations (eg, nonaffective psychosis [OR, 2.9; 95% CI, 1.2-7.0]). A total of 52.9% of posthospitalization suicides occurred after the 5% of hospitalizations with highest predicted suicide risk (3824.1 suicides per 100,000 person-years). These highest-risk hospitalizations also accounted for significantly elevated proportions of several other adverse posthospitalization outcomes (unintentional injury deaths, suicide attempts, and subsequent hospitalizations).Conclusions and relevanceThe high concentration of risk of suicide and other adverse outcomes might justify targeting expanded posthospitalization interventions to soldiers classified as having highest posthospitalization suicide risk, although final determination requires careful consideration of intervention costs, comparative effectiveness, and possible adverse effects.

Dataset Information

Genome-wide association study of shared liability to anxiety disorders in Army STARRS.

Publications

Genome-wide association study of shared liability to anxiety disorders in Army STARRS.

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