Genome-wide association study of shared liability to anxiety disorders in Army STARRS.
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ABSTRACT:
SUBMITTER: Hettema JM
PROVIDER: S-EPMC7210051 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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.
| S-EPMC4124912 | biostudies-literature
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.
| S-EPMC9800371 | biostudies-literature
Project description:Anxiety disorders (ADs), namely generalized AD, panic disorder and phobias, are common, etiologically complex conditions with a partially genetic basis. Despite differing on diagnostic definitions based on clinical presentation, ADs likely represent various expressions of an underlying common diathesis of abnormal regulation of basic threat-response systems. We conducted genome-wide association analyses in nine samples of European ancestry from seven large, independent studies. To identify genetic variants contributing to genetic susceptibility shared across interview-generated DSM-based ADs, we applied two phenotypic approaches: (1) comparisons between categorical AD cases and supernormal controls, and (2) quantitative phenotypic factor scores (FS) derived from a multivariate analysis combining information across the clinical phenotypes. We used logistic and linear regression, respectively, to analyze the association between these phenotypes and genome-wide single nucleotide polymorphisms. Meta-analysis for each phenotype combined results across the nine samples for over 18 000 unrelated individuals. Each meta-analysis identified a different genome-wide significant region, with the following markers showing the strongest association: for case-control contrasts, rs1709393 located in an uncharacterized non-coding RNA locus on chromosomal band 3q12.3 (P=1.65 × 10(-8)); for FS, rs1067327 within CAMKMT encoding the calmodulin-lysine N-methyltransferase on chromosomal band 2p21 (P=2.86 × 10(-9)). Independent replication and further exploration of these findings are needed to more fully understand the role of these variants in risk and expression of ADs.
| S-EPMC4940340 | biostudies-literature
Project description:The prevalence of 30-day mental disorders with retrospectively reported early onsets is significantly higher in the U.S. Army than among socio-demographically matched civilians. This difference could reflect high prevalence of preenlistment disorders and/or high persistence of these disorders in the context of the stresses associated with military service. These alternatives can to some extent be distinguished by estimating lifetime disorder prevalence among new Army recruits.The New Soldier Study (NSS) in the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) used fully structured measures to estimate lifetime prevalence of 10 DSM-IV disorders in new soldiers reporting for Basic Combat Training in 2011-2012 (n = 38,507). Prevalence was compared to estimates from a matched civilian sample. Multivariate regression models examined socio-demographic correlates of disorder prevalence and persistence among new soldiers.Lifetime prevalence of having at least one internalizing, externalizing, or either type of disorder did not differ significantly between new soldiers and civilians, although three specific disorders (generalized anxiety, posttraumatic stress, and conduct disorders) and multimorbidity were significantly more common among new soldiers than civilians. Although several socio-demographic characteristics were significantly associated with disorder prevalence and persistence, these associations were uniformly weak.New soldiers differ somewhat, but not consistently, from civilians in lifetime preenlistment mental disorders. This suggests that prior findings of higher prevalence of current disorders with preenlistment onsets among soldiers than civilians are likely due primarily to a more persistent course of early-onset disorders in the context of the special stresses experienced by Army personnel.
| S-EPMC5111824 | biostudies-literature
Project description:BackgroundAnxiety disorders are common, and cognitive-behavioural therapy (CBT) is a first-line treatment. Candidate gene studies have suggested a genetic basis to treatment response, but findings have been inconsistent.AimsTo perform the first genome-wide association study (GWAS) of psychological treatment response in children with anxiety disorders (n = 980).MethodPresence and severity of anxiety was assessed using semi-structured interview at baseline, on completion of treatment (post-treatment), and 3 to 12 months after treatment completion (follow-up). DNA was genotyped using the Illumina Human Core Exome-12v1.0 array. Linear mixed models were used to test associations between genetic variants and response (change in symptom severity) immediately post-treatment and at 6-month follow-up.ResultsNo variants passed a genome-wide significance threshold (P = 5 × 10(-8)) in either analysis. Four variants met criteria for suggestive significance (P<5 × 10(-6)) in association with response post-treatment, and three variants in the 6-month follow-up analysis.ConclusionsThis is the first genome-wide therapygenetic study. It suggests no common variants of very high effect underlie response to CBT. Future investigations should maximise power to detect single-variant and polygenic effects by using larger, more homogeneous cohorts.
| S-EPMC5007453 | biostudies-literature
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.
| S-EPMC6990967 | biostudies-literature
Project description:The 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.To 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.There 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.Suicides of soldiers hospitalized with psychiatric disorders in the 12 months after hospital discharge.Sixty-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).The 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.
| S-EPMC4286426 | biostudies-literature
Project description:There is mounting evidence that seemingly diverse psychiatric disorders share genetic etiology, but the biological substrates mediating this overlap are not well characterized. Here we leverage the unique Integrative Psychiatric Research Consortium (iPSYCH) study, a nationally representative cohort ascertained through clinical psychiatric diagnoses indicated in Danish national health registers. We confirm previous reports of individual and cross-disorder single-nucleotide polymorphism heritability for major psychiatric disorders and perform a cross-disorder genome-wide association study. We identify four novel genome-wide significant loci encompassing variants predicted to regulate genes expressed in radial glia and interneurons in the developing neocortex during mid-gestation. This epoch is supported by partitioning cross-disorder single-nucleotide polymorphism heritability, which is enriched at regulatory chromatin active during fetal neurodevelopment. These findings suggest that dysregulation of genes that direct neurodevelopment by common genetic variants may result in general liability for many later psychiatric outcomes.
| S-EPMC6497521 | biostudies-literature
Project description:Responding to an unprecedented increase in the suicide rate among soldiers, in 2008 the US Army and US National Institute of Mental Health funded the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS), a multicomponent epidemiological and neurobiological study of risk and resilience factors for suicidal thoughts and behaviors, and their psychopathological correlates among Army personnel. Using a combination of administrative records, representative surveys, computerized neurocognitive tests, and blood samples, Army STARRS and its longitudinal follow-up study (STARRS-LS) are designed to identify potentially actionable findings to inform the Army's suicide prevention efforts. The current report presents a broad overview of Army STARRS and its findings to date on suicide deaths, attempts, and ideation, as well as other important outcomes that may increase suicide risk (e.g., mental disorders, sexual assault victimization). The findings highlight the complexity of environmental and genetic risk and protective factors in different settings and contexts, and the importance of life and career history in understanding suicidal thoughts and behaviors.
| S-EPMC6756108 | biostudies-literature
Project description:ImportanceAnxiety 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.ObjectivesTo 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, participantsThis 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 measuresDiagnoses of a relatively broad diagnostic spectrum of anxiety and stress-related disorders.ResultsThe 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 relevanceThis 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.
| S-EPMC6537792 | biostudies-literature