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Background: Veterans of the 1990-1991 Gulf War have experienced excess health problems, most prominently the multisymptom condition Gulf War illness (GWI). The Department of Veterans Affairs (VA) Cooperative Studies Program #2006 "Genomics of Gulf War Illness in Veterans" project was established to address important questions concerning pathobiological and genetic aspects of GWI. The current study evaluated patterns of chronic ill health/GWI in the VA Million Veteran Program (MVP) Gulf War veteran cohort in relation to wartime exposures and key features of deployment, 27-30 years after Gulf War service., Methods: MVP participants who served in the 1990-1991 Gulf War completed the MVP Gulf War Era Survey in 2018-2020. Survey responses provided detailed information on veterans' health, Gulf War exposures, and deployment time periods and locations. Analyses determined associations of three defined GWI/ill health outcomes with Gulf War deployment characteristics and exposures., Results: The final cohort included 14,103 veterans; demographic and military characteristics of the sample were similar to the full population of U.S. 1990-1991 Gulf War veterans. Overall, a substantial number of veterans experienced chronic ill health, as indicated by three defined outcomes: 49% reported their health as fair or poor, 31% met Centers for Disease Control and Prevention criteria for severe GWI, and 20% had been diagnosed with GWI by a healthcare provider. Health outcomes varied consistently with veterans' demographic and military characteristics, and with exposures during deployment. All outcomes were most prevalent among youngest veterans (< 50 years), Army and Marine Corps veterans, enlisted personnel (vs. officers), veterans located in Iraq and/or Kuwait for at least 7 days, and veterans who remained in theater from January/February 1991 through the summer of 1991. In multivariable models, GWI/ill health was most strongly associated with three exposures: chemical/biological warfare agents, taking pyridostigmine bromide pills, and use of skin pesticides., Conclusions: Results from this large cohort indicate that GWI/chronic ill health continues to affect a large proportion of Gulf War veterans in patterns associated with 1990-1991 Gulf War deployment and exposures. Findings establish a foundation for comprehensive evaluation of genetic factors and deployment exposures in relation to GWI risk and pathobiology., (© 2024. The Author(s).)

Background: Nirmatrelvir-ritonavir is recommended for persons at risk for severe coronavirus disease 2019 (COVID-19) but remains underutilized. Information on which eligible groups are likely to benefit from treatment is needed., Methods: We conducted a target trial emulation study in the Veterans Health Administration comparing nirmatrelvir-ritonavir treated versus matched untreated veterans at risk for severe COVID-19 who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from April 2022 through March 2023. We measured incidence of any hospitalization or all-cause mortality at 30 days. Outcomes were measured for the entire cohort, as well as among subgroups defined by 30-day risk of death or hospitalization, estimated using an ensemble risk prediction model., Results: Participants were 87% male with median age 66 years and 16% unvaccinated. Compared with matched untreated participants, those treated with nirmatrelvir-ritonavir (n = 24 205) had a lower 30-day risk for hospitalization (1.80% vs 2.30%; risk difference [RD], -0.50% points [95% confidence interval {CI}: -.69 to -.35]) and death (0.11% vs 0.30%; RD, -0.20 [95% CI: -.24 to -.13]). The greatest reductions in combined hospitalization or death were observed in the highest risk quartile (RD -2.85 [95% CI: -3.94 to -1.76]), immunocompromised persons (RD -1.91 [95% CI: -3.09 to -.74]), and persons aged ≥75 years (RD -1.16 [95% CI: -1.73 to -.59]). No reductions were observed in the 2 lowest risk quartiles or persons younger than 65 years., Conclusions: Nirmatrelvir-ritonavir was effective in reducing 30-day hospitalization and death in older veterans, those at highest predicted risk for severe outcomes, and immunocompromised groups. Benefit was not observed in younger veterans or groups at lower predicted risk for hospitalization and death., Competing Interests: Potential conflicts of interest. D. H. reports consulting fees from Quality Insights, research consulting co-ownership in Van-Breemen & Hynes, LLC, and a subcontract at Oregon State University for a PCORI grant through the University of North Carolina, grants from VA Health Services Research and Development (HSRD), Quality Insight. G. I. reports grants from Department of Veterans Affairs. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

Persons diagnosed with schizophrenia (SCZ) or bipolar I disorder (BPI) are at high risk for self-injurious behavior, suicidal ideation, and suicidal behaviors (SB). Characterizing associations between diagnosed health problems, prior pharmacological treatments, and polygenic scores (PGS) has potential to inform risk stratification. We examined self-reported SB and ideation using the Columbia Suicide Severity Rating Scale (C-SSRS) among 3,942 SCZ and 5,414 BPI patients receiving care within the Veterans Health Administration (VHA). These cross-sectional data were integrated with electronic health records (EHRs), and compared across lifetime diagnoses, treatment histories, follow-up screenings, and mortality data. PGS were constructed using available genomic data for related traits. Genome-wide association studies were performed to identify and prioritize specific loci. Only 20% of the veterans who reported SB had a corroborating ICD-9/10 EHR code. Among those without prior SB, more than 20% reported new-onset SB at follow-up. SB were associated with a range of additional clinical diagnoses, and with treatment with specific classes of psychotropic medications (e.g., antidepressants, antipsychotics, etc.). PGS for externalizing behaviors, smoking initiation, suicide attempt, and major depressive disorder were associated with SB. The GWAS for SB yielded no significant loci. Among individuals with a diagnosed mental illness, self-reported SB were strongly associated with clinical variables across several EHR domains. Analyses point to sequelae of substance-related and psychiatric comorbidities as strong correlates of prior and subsequent SB. Nonetheless, past SB was frequently not documented in health records, underscoring the value of regular screening with direct, in-person assessments, especially among high-risk individuals., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Importance: Many psychiatric outcomes share a common etiologic pathway reflecting behavioral disinhibition, generally referred to as externalizing (EXT) disorders. Recent genome-wide association studies (GWASs) have demonstrated the overlap between EXT disorders and important aspects of veterans' health, such as suicide-related behaviors and substance use disorders (SUDs)., Objective: To explore correlates of risk for EXT disorders within the Veterans Health Administration (VA) Million Veteran Program (MVP)., Design, Setting, and Participants: A series of phenome-wide association studies (PheWASs) of polygenic risk scores (PGSs) for EXT disorders was conducted using electronic health records. First, ancestry-specific PheWASs of EXT PGSs were conducted in the African, European, and Hispanic or Latin American ancestries. Next, a conditional PheWAS, covarying for PGSs of comorbid psychiatric problems (depression, schizophrenia, and suicide attempt; European ancestries only), was performed. Lastly, to adjust for unmeasured confounders, a within-family analysis of significant associations from the main PheWAS was performed in full siblings (European ancestries only). This study included the electronic health record data from US veterans from VA health care centers enrolled in MVP. Analyses took place from February 2022 to August 2023 covering a period from October 1999 to January 2020., Exposures: PGSs for EXT, depression, schizophrenia, and suicide attempt., Main Outcomes and Measures: Phecodes for diagnoses derived from the International Statistical Classification of Diseases, Ninth and Tenth Revisions, Clinical Modification, codes from electronic health records., Results: Within the MVP (560 824 patients; mean [SD] age, 67.9 [14.3] years; 512 593 male [91.4%]), the EXT PGS was associated with 619 outcomes, of which 188 were independent of risk for comorbid problems or PGSs (from odds ratio [OR], 1.02; 95% CI, 1.01-1.03 for overweight/obesity to OR, 1.44; 95% CI, 1.42-1.47 for viral hepatitis C). Of the significant outcomes, 73 (11.9%) were significant in the African results and 26 (4.5%) were significant in the Hispanic or Latin American results. Within-family analyses uncovered robust associations between EXT PGS and consequences of SUDs, including liver disease, chronic airway obstruction, and viral hepatitis C., Conclusions and Relevance: Results of this cohort study suggest a shared polygenic basis of EXT disorders, independent of risk for other psychiatric problems. In addition, this study found associations between EXT PGS and diagnoses related to SUDs and their sequelae. Overall, this study highlighted the potential negative consequences of EXT disorders for health and functioning in the US veteran population.

To address gaps in understanding the pathophysiology of Gulf War Illness (GWI), the VA Million Veteran Program (MVP) developed and implemented a survey to MVP enrollees who served in the U.S. military during the 1990-1991 Persian Gulf War (GW). Eligible Veterans were invited via mail to complete a survey assessing health conditions as well as GW-specific deployment characteristics and exposures. We evaluated the representativeness of this GW-era cohort relative to the broader population by comparing demographic, military, and health characteristics between respondents and non-respondents, as well as with all GW-era Veterans who have used Veterans Health Administration (VHA) services and the full population of U.S. GW-deployed Veterans. A total of 109,976 MVP GW-era Veterans were invited to participate and 45,270 (41%) returned a completed survey. Respondents were 84% male, 72% White, 8% Hispanic, with a mean age of 61.6 years ( SD = 8.5). Respondents were more likely to be older, White, married, better educated, slightly healthier, and have higher socioeconomic status than non-respondents, but reported similar medical conditions and comparable health status. Although generally similar to all GW-era Veterans using VHA services and the full population of U.S. GW Veterans, respondents included higher proportions of women and military officers, and were slightly older. In conclusion, sample characteristics of the MVP GW-era cohort can be considered generally representative of the broader GW-era Veteran population. The sample represents the largest research cohort of GW-era Veterans established to date and provides a uniquely valuable resource for conducting in-depth studies to evaluate health conditions affecting 1990-1991 GW-era Veterans.

Affecting an estimated 88 million Americans, prediabetes increases the risk for developing type 2 diabetes mellitus (T2DM), and independently, cardiovascular disease, retinopathy, nephropathy, and neuropathy. Nevertheless, little is known about the use of metformin for diabetes prevention among patients in the Veterans Health Administration, the largest integrated healthcare system in the U.S. This is a retrospective observational cohort study of the proportion of Veterans with incident prediabetes who were prescribed metformin at the Veterans Health Administration from October 2010 to September 2019. Among 1,059,605 Veterans with incident prediabetes, 12,009 (1.1%) were prescribed metformin during an average 3.4 years of observation after diagnosis. Metformin prescribing was marginally higher (1.6%) among those with body mass index (BMI) ≥35 kg/m 2 , age <60 years, HbA 1c ≥6.0%, or those with a history of gestational diabetes, all subgroups at a higher risk for progression to T2DM. In a multivariable model, metformin was more likely to be prescribed for those with BMI ≥35 kg/m 2 incidence rate ratio [IRR] 2.6 [95% confidence intervals (CI): 2.1-3.3], female sex IRR, 2.4 [95% CI: 1.8-3.3], HbA 1c ≥6% IRR, 1.93 [95% CI: 1.5-2.4], age <60 years IRR, 1.7 [95% CI: 1.3-2.3], hypertriglyceridemia IRR, 1.5 [95% CI: 1.2-1.9], hypertension IRR, 1.5 [95% CI: 1.1-2.1], Major Depressive Disorder IRR, 1.5 [95% CI: 1.1-2.0], or schizophrenia IRR, 2.1 [95% CI: 1.2-3.8]. Over 20% of Veterans with prediabetes attended a comprehensive structured lifestyle modification clinic or program. Among Veterans with prediabetes, metformin was prescribed to 1.1% overall, a proportion that marginally increased to 1.6% in the subset of individuals at highest risk for progression to T2DM., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: COVID-19 has been linked to the development of many post-COVID-19 conditions (PCCs) after acute infection. Limited information is available on the effectiveness of oral antivirals used to treat acute COVID-19 in preventing the development of PCCs., Objective: To measure the effectiveness of outpatient treatment of COVID-19 with nirmatrelvir-ritonavir in preventing PCCs., Design: Retrospective target trial emulation study comparing matched cohorts receiving nirmatrelvir-ritonavir versus no treatment., Setting: Veterans Health Administration (VHA)., Participants: Nonhospitalized veterans in VHA care who were at risk for severe COVID-19 and tested positive for SARS-CoV-2 during January through July 2022., Intervention: Nirmatrelvir-ritonavir treatment for acute COVID-19., Measurements: Cumulative incidence of 31 potential PCCs at 31 to 180 days after treatment or a matched index date, including cardiac, pulmonary, renal, thromboembolic, gastrointestinal, neurologic, mental health, musculoskeletal, endocrine, and general conditions and symptoms., Results: Eighty-six percent of the participants were male, with a median age of 66 years, and 17.5% were unvaccinated. Baseline characteristics were well balanced between participants treated with nirmatrelvir-ritonavir and matched untreated comparators. No differences were observed between participants treated with nirmatrelvir-ritonavir ( n = 9593) and their matched untreated comparators in the incidence of most PCCs examined individually or grouped by organ system, except for lower combined risk for venous thromboembolism and pulmonary embolism (subhazard ratio, 0.65 [95% CI, 0.44 to 0.97]; cumulative incidence difference, -0.29 percentage points [CI, -0.52 to -0.05 percentage points])., Limitations: Ascertainment of PCCs using International Classification of Diseases, 10th Revision, codes may be inaccurate. Evaluation of many outcomes could have resulted in spurious associations with combined thromboembolic events by chance., Conclusion: Out of 31 potential PCCs, only combined thromboembolic events seemed to be reduced by nirmatrelvir-ritonavir., Primary Funding Source: U.S. Department of Veterans Affairs., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-1394.

Importance: Several pharmacotherapies have been authorized to treat nonhospitalized persons with symptomatic COVID-19. Longitudinal information on the use of these therapies is needed., Objective: To analyze trends and factors associated with prescription of outpatient COVID-19 pharmacotherapies within the Veterans Health Administration (VHA)., Design, Setting, and Participants: This cohort study evaluated nonhospitalized veterans in VHA care who tested positive for SARS-CoV-2 from January 2022 through January 2023 using VHA and linked Community Care and Medicare databases., Exposures: Demographic characteristics, underlying medical conditions, COVID-19 vaccination, and regional and local systems of care, including Veterans Integrated Services Networks (VISNs)., Main Outcomes and Measures: Monthly receipt of any COVID-19 pharmacotherapy (nirmatrelvir-ritonavir, molnupiravir, sotrovimab, or bebtelovimab) was described. Multivariable logistic regression was used to identify factors independently associated with receipt of any vs no COVID-19 pharmacotherapy., Results: Among 285 710 veterans (median [IQR] age, 63.1 [49.9-73.7] years; 247 358 males [86.6%]; 28 444 Hispanic [10.0%]; 61 269 Black [21.4%] and 198 863 White [69.6%]) who tested positive for SARS-CoV-2 between January 2022 and January 2023, the proportion receiving any pharmacotherapy increased from 3285 of 102 343 veterans (3.2%) in January 2022 to 5180 of 21 688 veterans (23.9%) in August 2022. The proportion declined to 2194 of 10 551 veterans (20.8%) by January 2023. Across VISNs, the range in proportion of patients who tested positive who received nirmatrelvir-ritonavir or molnupiravir during January 2023 was 41 of 692 veterans (5.9%) to 106 of 494 veterans (21.4%) and 2.1% to 120 of 1074 veterans (11.1%), respectively. Veterans receiving any treatment were more likely to be older (adjusted odds ratio [aOR] for ages 65-74 vs 50-64 years, 1.18; 95% CI, 1.14-1.22; aOR for ages ≥75 vs 50-64 years, 1.19; 95% CI, 1.15-1.23) and have a higher Charlson Comorbidity Index score (aOR for CCI ≥6 vs 0, 1.52; 95% CI, 1.44-1.59). Compared with White veterans, Black veterans (aOR, 1.06; 95% CI, 1.02-1.09) were more likely to receive treatment, and compared with non-Hispanic veterans, Hispanic veterans (aOR 1.06; 95% CI, 1.01-1.11) were more likely to receive treatment., Conclusions and Relevance: This study found that prescription of outpatient COVID-19 pharmacotherapies in the VHA peaked in August 2022 and declined thereafter. There were large regional differences in patterns of nirmatrelvir-ritonavir and molnupiravir use.

Background: The Million Veteran Program (MVP) participants represent 100 years of US history, including significant social and demographic changes over time. Our study assessed two aspects of the MVP: (i) longitudinal changes in population diversity and (ii) how these changes can be accounted for in genome-wide association studies (GWAS). To investigate these aspects, we divided MVP participants into five birth cohorts (N-range = 123,888 [born from 1943 to 1947] to 136,699 [born from 1948 to 1953])., Results: Ancestry groups were defined by (i) HARE (harmonized ancestry and race/ethnicity) and (ii) a random-forest clustering approach using the 1000 Genomes Project and the Human Genome Diversity Project (1kGP + HGDP) reference panels (77 world populations representing six continental groups). In these groups, we performed GWASs of height, a trait potentially affected by population stratification. Birth cohorts demonstrate important trends in ancestry diversity over time. More recent HARE-assigned Europeans, Africans, and Hispanics had lower European ancestry proportions than older birth cohorts (0.010 < Cohen's d < 0.259, p < 7.80 × 10 -4 ). Conversely, HARE-assigned East Asians showed an increase in European ancestry proportion over time. In GWAS of height using HARE assignments, genomic inflation due to population stratification was prevalent across all birth cohorts (linkage disequilibrium score regression intercept = 1.08 ± 0.042). The 1kGP + HGDP-based ancestry assignment significantly reduced the population stratification (mean intercept reduction = 0.045 ± 0.007, p < 0.05) confounding in the GWAS statistics., Conclusions: This study provides a characterization of ancestry diversity of the MVP cohort over time and compares two strategies to infer genetically defined ancestry groups by assessing differences in controlling population stratification in genome-wide association studies., (© 2023. The Author(s).)

Background: Information about the effectiveness of oral antivirals in preventing short- and long-term COVID-19-related outcomes in the setting of Omicron variant transmission and COVID-19 vaccination is limited., Objective: To measure the effectiveness of nirmatrelvir-ritonavir and molnupiravir for outpatient treatment of COVID-19., Design: Three retrospective target trial emulation studies comparing matched cohorts of nirmatrelvir-ritonavir versus no treatment, molnupiravir versus no treatment, and nirmatrelvir-ritonavir versus molnupiravir., Setting: Veterans Health Administration (VHA)., Participants: Nonhospitalized veterans in VHA care who were at risk for severe COVID-19 and tested positive for SARS-CoV-2 during January through July 2022., Intervention: Nirmatrelvir-ritonavir or molnupiravir pharmacotherapy., Measurements: Incidence of any hospitalization or all-cause mortality at 30 days and from 31 to 180 days., Results: Eighty-seven percent of participants were male; the median age was 66 years, and 18% were unvaccinated. Compared with matched untreated control participants, those treated with nirmatrelvir-ritonavir ( n  = 9607) had lower 30-day risk for hospitalization (22.07 vs. 30.32 per 1000 participants; risk difference [RD], -8.25 [95% CI, -12.27 to -4.23] per 1000 participants) and death (1.25 vs. 5.47 per 1000 participants; RD, -4.22 [CI, -5.45 to -3.00] per 1000 participants). Among persons alive at day 31, reductions were seen in 31- to 180-day incidence of death (hazard ratio, 0.66 [CI, 0.49 to 0.89]) but not hospitalization (subhazard ratio, 0.90 [CI, 0.79 to 1.02]). Molnupiravir-treated participants ( n  = 3504) had lower 30-day and 31- to 180-day risks for death (3.14 vs. 13.56 per 1000 participants at 30 days; RD, -10.42 [CI, -13.49 to -7.35] per 1000 participants; hazard ratio at 31 to 180 days, 0.67 [CI, 0.48 to 0.95]) but not hospitalization. A difference in 30-day or 31- to 180-day risk for hospitalization or death was not observed between matched nirmatrelvir- or molnupiravir-treated participants., Limitation: The date of COVID-19 symptom onset for most veterans was unknown., Conclusion: Nirmatrelvir-ritonavir was effective in reducing 30-day hospitalization and death. Molnupiravir was associated with a benefit for 30-day mortality but not hospitalization. Further reductions in mortality from 31 to 180 days were observed with both antivirals., Primary Funding Source: U.S. Department of Veterans Affairs., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M22-3565.

Gulf War Illness (GWI), a chronic multisymptom illness with a complex and uncertain etiology and pathophysiology, is highly prevalent among veterans deployed to the 1990-1991 GW. We examined how GWI phenotypes varied by demographic and military characteristics among GW-era veterans. Data were from the VA's Cooperative Studies Program 2006/Million Veteran Program (MVP) 029 cohort, Genomics of GWI. From June 2018 to March 2019, 109,976 MVP enrollees (out of a total of over 676,000) were contacted to participate in the 1990-1991 GW-era Survey. Of 109,976 eligible participants, 45,169 (41.1%) responded to the 2018-2019 survey, 35,902 respondents met study inclusion criteria, 13,107 deployed to the GW theater. GWI phenotypes were derived from Kansas (KS) and Centers for Disease Control and Prevention (CDC) GWI definitions: (a) KS Symptoms (KS Sym+), (b) KS GWI (met symptom criteria and without exclusionary health conditions) [KS GWI: Sym+/Dx-], (c) CDC GWI and (d) CDC GWI Severe. The prevalence of each phenotype was 67.1% KS Sym+, 21.5% KS Sym+/Dx-, 81.1% CDC GWI, and 18.6% CDC GWI severe. These findings affirm the persistent presence of GWI among GW veterans providing a foundation for further exploration of biological and environmental underpinnings of this condition.

Importance: Older adults and individuals with medical comorbidities are at increased risk for severe COVID-19. Several pharmacotherapies demonstrated to reduce the risk of COVID-19-related hospitalization and death have been authorized for use., Objective: To describe factors associated with receipt of outpatient COVID-19 pharmacotherapies in the Veterans Affairs (VA) health care system., Design, Settings, and Participants: This cohort study assessed outpatient veterans with risk factors for severe COVID-19 who tested positive for SARS-CoV-2 during January and February 2022. The setting was the VA health care system, the largest integrated health care system in the US., Exposures: Demographic characteristics, place of residence, underlying medical conditions, and COVID-19 vaccination., Main Outcomes and Measures: The odds of receipt of any COVID-19 pharmacotherapy, including sotrovimab, nirmatrelvir boosted with ritonavir, molnupiravir, or remdesivir were estimated using multivariable logistic regression., Results: Among 111 717 veterans included in this study (median [IQR] age, 60 [46-72] years; 96 482 [86.4%] male, 23 362 [20.9%] Black, 10 740 [9.6%] Hispanic, 75 973 [68.0%] White) who tested positive for SARS-CoV-2 during January to February 2022, 4233 (3.8%) received any COVID-19 pharmacotherapy, including 2870 of 92 396 (3.1%) in January and 1363 of 19 321 (7.1%) in February. Among a subset of 56 285 veterans with documented COVID-19-related symptoms in the 30 days preceding a positive SARS-CoV-2 test, 3079 (5.5%) received any COVID-19 pharmacotherapy. Untreated veterans had a median (IQR) age of 60 (46-71) years and a median (IQR) of 3 (2-5) underlying medical conditions. Veterans receiving any treatment were more likely to be older (aged 65 to 74 years vs 50 to 64 years: adjusted odds ratio [aOR], 1.66 [95% CI, 1.52-1.80]; aged at least 75 years vs 50 to 64 years: aOR, 1.67 [95% CI, 1.53-1.84]) and have a higher number of underlying conditions (at least 5 conditions vs 1 to 2 conditions: aOR, 2.17 [95% CI, 1.98-2.39]). Compared with White veterans, Black veterans (aOR, 0.65 [95% CI, 0.60-0.72]) were less likely to receive treatment; and compared with non-Hispanic veterans, Hispanic veterans (aOR, 0.88 [95% CI, 0.77-0.99]) were less likely to receive treatment. There were 16 546 courses of sotrovimab, nirmatrelvir, and molnupiravir allocated across the VA during this period., Conclusions and Relevance: In this cohort study of veterans who tested positive for SARS-CoV-2 during January and February when supply of outpatient COVID-19 pharmacotherapies was limited, prescription of these pharmacotherapies was underused, and many veterans with risk factors for severe COVID-19 did not receive treatment. Veterans from minority racial and ethnic groups were less likely to receive any pharmacotherapy.

Cross-sectional research suggests that posttraumatic stress symptoms (PTSS) among war zone veterans are associated with functional impairment and poor quality of life. Less is known about the long-term functional repercussions of PTSS. This study of Iraq War veterans examined the associations between increases in PTSS and long-term functional outcomes, including the potential contributions of neurocognitive decrements. Service members and veterans (N = 594) completed self-report measures of functioning and PTSS severity before Iraq War deployment and again after their return (M = 9.3 years postdeployment). Some participants (n = 278) also completed neurocognitive testing at both times. Multiple regression analyses with the full sample-adjusted for TBI, demographic characteristics, military variables, and predeployment PTSS and functioning-revealed that increased PTSS severity over time was significantly associated with unemployment, aOR = 1.04, 95% CI [1.03, 1.06]; poorer work performance; and poorer physical, emotional, and cognitive health-related functioning at long-term follow-up, f 2 s = 0.37-1.79. Among participants who completed neurocognitive testing, a decline in select neurocognitive measures was associated with poorer functioning; however, neurocognitive decrements did not account for associations between increased PTSS and unemployment, aOR = 1.04, 95% CI [1.02, 1.07], with the size and direction upheld after adding neurocognitive variables, or poorer functional outcomes, with small increases after adding neurocognitive measures to the models, f 2 s = 0.03-0.10. War zone veterans experiencing long-term increased PTSS and/or neurocognitive decrements may be at elevated risk for higher-level functional impairment over time, suggesting that early PTSS management may enhance long-term functioning., (Published 2021. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Schizophrenia (SCZ) and bipolar disorder (BIP) are debilitating neuropsychiatric disorders, collectively affecting 2% of the world's population. Recognizing the major impact of these psychiatric disorders on the psychosocial function of more than 200 000 US Veterans, the Department of Veterans Affairs (VA) recently completed genotyping of more than 8000 veterans with SCZ and BIP in the Cooperative Studies Program (CSP) #572., Methods: We performed genome-wide association studies (GWAS) in CSP #572 and benchmarked the predictive value of polygenic risk scores (PRS) constructed from published findings. We combined our results with available summary statistics from several recent GWAS, realizing the largest and most diverse studies of these disorders to date., Results: Our primary GWAS uncovered new associations between CHD7 variants and SCZ, and novel BIP associations with variants in Sortilin Related VPS10 Domain Containing Receptor 3 (SORCS3) and downstream of PCDH11X. Combining our results with published summary statistics for SCZ yielded 39 novel susceptibility loci including CRHR1, and we identified 10 additional findings for BIP (28 326 cases and 90 570 controls). PRS trained on published GWAS were significantly associated with case-control status among European American (P < 10-30) and African American (P < .0005) participants in CSP #572., Conclusions: We have demonstrated that published findings for SCZ and BIP are robustly generalizable to a diverse cohort of US veterans. Leveraging available summary statistics from GWAS of global populations, we report 52 new susceptibility loci and improved fine-mapping resolution for dozens of previously reported associations., (Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center 2020.)

Objective: Many veterans of the Iraq and Afghanistan Wars have experienced traumatic brain injury (TBI). Although prior work has examined associations between TBI and development of psychiatric syndromes, less is known about associations between TBI and component emotions constituting these syndromes, especially in the long term. The purpose of this study was to examine the long-term emotional consequences of deployment-related TBI., Methods: As part of VA Cooperative Studies Program #566, we assessed a sample of n  = 456 US Army soldiers prior to an index deployment to Iraq, and again an average of 8.3 years ( SD  = 2.4 years) after their deployment for a long-term follow-up assessment. In this report, we used adjusted regression analyses to examine the relationship of deployment TBI to depression, anxiety, and stress symptom severity measured at the long-term follow-up assessment. A structured interview was used to determine TBI history; the Depression, Anxiety, and Stress Scale, 21-item version (DASS-21) was used to determine emotional status at the follow-up evaluation., Results: Warzone TBI events, particularly when greater than mild in severity, were independently associated with depression, anxiety, and stress severity at long-term follow-up, even after taking into account variance attributable to pre-deployment emotional distress and war-zone stress. Post-hoc analyses did not detect independent associations of either number of events or injury mechanism with outcomes., Conclusions: These findings highlight the potentially enduring and multi-faceted emotional effects of deployment TBI, underscoring the need for early assessment of negative affectivity in warzone veterans reporting TBI.

Background: We compared male and female American veterans with schizophrenia or bipolar disorder regarding clinical characteristics associated with lifetime suicidal ideation and behavior. Subsequent mortality, including death by suicide, was also assessed., Methods: Data from questionnaires and face-to-face evaluations were collected during 2011-2014 from 8,049 male and 1,290 female veterans with schizophrenia or bipolar disorder. In addition to comparing male-female characteristics, Cox regression models-adjusted for demographic information, medical-psychiatric comorbidities, and self-reported suicidal ideation and behavior-were used to examine gender differences in associations of putative risk factors with suicide-specific and all-cause mortality during up to six years of follow-up., Results: Women overall were younger, more likely to report a history of suicidal behavior, less likely to be substance abusers, and had lower overall mortality during follow-up. Among women only, psychiatric comorbidity was paradoxically associated with lower all-cause mortality (hazard ratio [HR]=0.53, 95% CI, 0.29-0.96, p = 0.037 for 1 disorder vs. none; HR=0.44, 95% CI, 0.25-0.77, p = 0.004 for ≥2 disorders vs. none). Suicide-specific mortality involved relatively few events, but crude rates were an order of magnitude higher than in the U.S. general and overall veteran populations., Limitations: Incomplete cause-of-death information and low statistical power for male-female comparisons regarding mortality., Conclusions: Female veterans with SMI differed from females in the general population by having a higher risk of suicide attempts. They also had more lifetime suicide attempts than male veterans with same diagnoses. These differences should inform public policy and clinical planning., Competing Interests: Declaration of Competing Interest Dr. Harvey has received consulting fees or travel reimbursements from Boehringer Ingelheim, Intra-Cellular Therapies, Minerva, Otsuka America (Otsuka Digital Health), Sanofi Pharma, Sunovion Pharma, Takeda Pharma, and Teva during the past year. He receives royalties from the Brief Assessment of Cognition in Schizophrenia, and he has a research grant from Takeda and from the Stanley Medical Research Foundation. These activities are unrelated to the content of this paper., (Published by Elsevier B.V.)

We developed an algorithm for identifying U.S. veterans with a history of posttraumatic stress disorder (PTSD), using the Department of Veterans Affairs (VA) electronic medical record (EMR) system. This work was motivated by the need to create a valid EMR-based phenotype to identify thousands of cases and controls for a genome-wide association study of PTSD in veterans. We used manual chart review (n = 500) as the gold standard. For both the algorithm and chart review, three classifications were possible: likely PTSD, possible PTSD, and likely not PTSD. We used Lasso regression with cross-validation to select statistically significant predictors of PTSD from the EMR and then generate a predicted probability score of being a PTSD case for every participant in the study population (range: 0-1.00). Comparing the performance of our probabilistic approach (Lasso algorithm) to a rule-based approach (International Classification of Diseases [ICD] algorithm), the Lasso algorithm showed modestly higher overall percent agreement with chart review than the ICD algorithm (80% vs. 75%), higher sensitivity (0.95 vs. 0.84), and higher accuracy (AUC = 0.95 vs. 0.90). We applied a 0.7 probability cut-point to the Lasso results to determine final PTSD case-control status for the VA population. The final algorithm had a 0.99 sensitivity, 0.99 specificity, 0.95 positive predictive value, and 1.00 negative predictive value for PTSD classification (grouping possible PTSD and likely not PTSD) as determined by chart review. This algorithm may be useful for other research and quality improvement endeavors within the VA., (Published 2019. This article is a U.S. Government work and is in the public domain in the USA.)

Objectives: Heritability in the risk for developing posttraumatic stress disorder (PTSD) has been established, but most genome-wide association studies (GWASs) of PTSD involve relatively small sample sizes and limited identification of associated genetic loci. This report describes the methodology of a Veterans Affairs (VA) Cooperative Studies Program GWAS of PTSD among combat-exposed U.S. veterans., Methods: Probable cases (with PTSD) and probable controls (without PTSD) were identified from among veterans enrolled in the VA Million Veteran Program (MVP) with an algorithm developed using questionnaire responses and electronic health record information. This algorithm, based on a statistical model, relied on medical chart reviews as a reference standard and was refined using telephone interviews. Subsequently, to evaluate the impact of probabilistic phenotyping on statistical power, the threshold probability for case-control selection was varied in simulations., Results: As of September 2018, >695,000 veterans have enrolled in MVP. For current analyses, genotyping data were available for >353,000 participants, including >83,000 combat-exposed veterans. A threshold probability of 0.7 for case and control designation yielded an interim >16,000 cases and >33,000 controls., Conclusions: A formal methodological approach was used to identify cases and controls for subsequent GWAS analyses to identify genetic risk loci for PTSD., (© 2019 John Wiley & Sons, Ltd.)

The long-term mental health effects of war-zone deployment in the Iraq and Afghanistan wars on military personnel are a significant public health concern. Using data collected prospectively at three distinct assessments during 2003-2014 as part of the Neurocognition Deployment Health Study and VA Cooperative Studies Program Study #566, we explored how stress exposures prior, during, and after return from deployment influence the long-term mental health outcomes of posttraumatic stress disorder (PTSD), depression, anxiety disorders, and problem drinking. Longer-term mental health outcomes were assessed in 375 service members and military veterans an average of 7.5 years (standard deviation = 1.0 year) after the initial (i.e., "index") Iraq deployment following their predeployment assessment. Anxiety disorder was the most commonly observed long-term mental health outcome (36.0%), followed by depression (24.5%), PTSD (24.3%), and problem drinking (21.0%). Multivariable regression models showed that greater postdeployment stressors, as measured by the Post-Deployment Life Events scale, were associated with greater risk of depression, anxiety disorders, and problem drinking. Anxiety disorder was the only outcome affected by predeployment stress concerns. In addition, greater postdeployment social support was associated with lower risk of all outcomes except problem drinking. These findings highlight the importance of assessing postdeployment stress exposures, such as stressful or traumatic life events, given the potential impact of these stressors on long-term mental health outcomes. This study also highlights the importance of postdeployment social support as a modifiable protective factor that can be used to help mitigate risk of long-term adverse mental health outcomes following war-zone exposure., (Copyright © 2018. Published by Elsevier Ltd.)

Objectives: Military deployment is associated with increased risk of adverse emotional and cognitive outcomes. Longitudinal associations involving posttraumatic stress disorder (PTSD), relatively mild traumatic brain injury (TBI), and neurocognitive compromise are poorly understood, especially with regard to long-term outcomes, and rigorous research is necessary to better understand the corresponding relationships. The objective of this study was to examine short-term and long-term (>5 years) longitudinal associations among PTSD, neurocognitive performance, and TBI following military deployment., Methods: In this prospective study, N=315 U.S. Army soldiers were assessed at military installations before (2003-2005) and after (2004-2006) an index deployment to the Iraq War, and again an average of 7.6 years later (2010-2014) as a nationally dispersed cohort of active duty soldiers, reservists, and veterans. Thus, the study design allowed for two measurement intervals over which to examine changes. All assessments included the PTSD Checklist, civilian version, and individually-administered performance-based neurocognitive tests. TBI history was derived from clinical interview., Results: Autoregressive analyses indicated that visual reproduction scores were inversely related to subsequent PTSD symptom severity at subsequent assessments. Conversely, increases in PTSD symptom severity over each measurement interval were associated with poorer verbal and/or visual recall at the end of each interval, and less efficient reaction time at post-deployment. TBI, primarily mild in this sample, was associated with adverse PTSD symptom outcomes at both post-deployment and long-term follow-up., Conclusions: These results suggest longitudinal relationships among PTSD symptoms, TBI, and neurocognitive decrements may contribute to sustained emotional and neurocognitive symptoms over time. (JINS, 2018, 24, 311-323).

The mental health toll of the Iraq and Afghanistan Wars on military veterans has been considerable, yet little is known about the persistence of these adverse outcomes, especially relative to predeployment status. We prospectively examined posttraumatic stress disorder (PTSD) as a long-term consequence of warzone deployment, integrating data collected from 2003-2014. In the Neurocognition Deployment Health Study, we measured PTSD symptoms in US Army soldiers before and shortly after Iraq War deployment. We used the PTSD Checklist-Civilian Version and a structured clinical interview (i.e., Clinician-Administered PTSD Scale) to reassess PTSD in 598 service members and military veterans a median of 7.9 years (interquartile range, 7.2-8.5 years) after an index Iraq deployment. At long-term follow-up, 24.7% (95% confidence interval (CI): 21.5, 28.4) of participants met the case definition for PTSD, which was an absolute increase of 14.2% from the percentage assessed postdeployment (10.5%; 95% CI: 7.8, 13.7) and of 17.3% from the percentage assessed predeployment (7.4%; 95% CI: 5.5, 9.8). These findings highlight that PTSD is an enduring consequence of warzone participation among contemporary military personnel and veterans. The largest increase in PTSD cases occurred between the postdeployment and long-term follow-up assessments, which suggests that adverse stress reactions cannot necessarily be expected to dissipate over time and actually may increase., (Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Objective: To describe the design and ongoing conduct of the Million Veteran Program (MVP), as an observational cohort study and mega-biobank in the Department of Veterans Affairs (VA) health care system., Study Design and Setting: Data are being collected from participants using questionnaires, the VA electronic health record, and a blood sample for genomic and other testing. Several ongoing projects are linked to MVP, both as peer-reviewed research studies and as activities to help develop an infrastructure for future, broad-based research uses., Results: Formal planning for MVP commenced in 2009; the protocol was approved in 2010, and enrollment began in 2011. As of August 3, 2015, and with a steady state of ≈50 recruiting sites nationwide, N = 397,104 veterans have been enrolled. Among N = 199,348 with currently available genotyping data, most participants (as expected) are male (92.0%) between the ages of 50 and 69 years (55.0%). On the basis of self-reported race, white (77.2%) and African American (13.5%) populations are well represented., Conclusions: By helping to promote the future integration of genetic testing in health care delivery, including clinical decision making, the MVP is designed to contribute to the development of precision medicine., (Published by Elsevier Inc.)

Given the prominence of cognitive impairments and disability associated with schizophrenia and bipolar disorder, substantial interest has arisen in identifying determinants of the diseases and their features. Genetic variation has been linked to skills that underlie disability ("functional capacity" or FC), highlighting need for understanding of these relationships. We describe the design and methods of a large, multisite, observational study focusing on the genetics of functional disability in schizophrenia and bipolar disorder, presenting initial data on recruitment, and characterization of the sample. Known as Veterans Affairs (VA) Cooperative Studies Program (CSP)#572, this study is recruiting, diagnosing, and assessing U.S. Veterans with either schizophrenia or bipolar I disorder. Assessments include neuropsychological (NP) testing, FC, suicidality, and co-morbid conditions such as posttraumatic stress disorder (PTSD). A sample of "psychiatrically healthy" Veterans from another project serves as a comparison group. An interim total of 8,140 participants (42.1% schizophrenia) have been recruited and assessed as of September 30, 2013, with 9 months of enrollment remaining and with a target sample size of 9,500. Veterans with schizophrenia were more likely to never have married, whereas lifetime PTSD and suicidality were more common in the bipolar veterans. Performance on the FC measures and NP tests was consistent with previous results, with mean t-scores of 35 (-1.5 SD) for schizophrenia and 41 (-0.9 SD) for the bipolar Veterans. This large population is representative of previous studies in terms of patient performance and co-morbidities. Subsequent genomic analyses will examine the genomic correlates of performance-based measures. Published 2014. This article is a U.S. Government work and is in the public domain in the USA., (Published 2014 Wiley Periodicals, Inc.)

Background: Among men treated for prostate cancer, increasing prostate-specific antigen (PSA) is known as biochemical failure or biochemical recurrence (BCR). The impact of BCR on subsequent mortality is uncertain, however, especially given competing causes of death., Methods: To describe patterns of BCR and subsequent mortality, we conducted an observational study in a community-based, "high-comorbidity" setting of 623 US veterans diagnosed as having prostate cancer from 1991 to 1995 and receiving radical prostatectomy or radiation therapy. The main outcome measures were BCR, defined as a PSA level of 0.4 ng/mL or higher (treated with surgery) or "PSA nadir+2 ng/mL" (treated with radiation therapy), and prostate cancer mortality, determined through 2006., Results: With 5-, 10-, and 15-year follow-up periods, respectively (for all results shown herein), the cumulative incidence of BCR after prostatectomy (n=225) was 34%, 37%, and 37%; prostate cancer mortality among men who failed treatment (n=81) was 3%, 11%, and 21%. Among men receiving radiation therapy (n=398), the cumulative incidence of BCR was 35%, 46%, and 48%; prostate cancer mortality among those who failed treatment (n=161) was 11%, 20%, and 42%. Overall, BCR was associated with an increased risk of death from prostate cancer in the study population, but the individual probability of this outcome was relatively low., Conclusions: Biochemical recurrence is associated with increased prostate cancer mortality, yet when BCR occurs only a minority of men subsequently die of their disease. The phrase "most men die with prostate cancer, not of it" applies to elderly veterans, even after failure of primary treatment. New strategies for defining and managing treatment failure in prostate cancer are needed.

Background: Factors affecting acetylcholine-mediated neurotransmission have been proposed as possible explanations for physical and mental health symptoms among veterans of the 1990-1991 Gulf War. This study was designed to examine relationships of deployment to the Gulf, as well as symptoms after military service, with postdeployment activity of acetylcholinesterase (AChE) and related enzymes., Methods: The patient population included 488 veterans, originally from Iowa at enlistment, who served in the US military during August 1990 to July 1991. Demographic, military, and clinical characteristics were obtained from a population-based cohort study (in 1995-1996) and from a nested case-control study (in 1999-2002). Stored serum samples (from the 1999-2002 assessment) were analyzed for activity of AChE and related enzymes. These two data sources were merged, and multiple linear regression models estimated the association of deployment, stress (anxiety) or mood disorders, and symptoms compatible with Gulf War veterans' illnesses (GWVIs), with enzyme activity., Results: Seventy-four percent (n = 361) of veterans had been deployed to the Gulf. At the time of evaluation, 23% (n = 113) of participants reported anxiety and 15% (n = 71) reported mood disorders; 49% (n = 171 of 347 eligible veterans) had symptoms of GWVIs, and the median AChE activity was 839 units. AChE activity was similar for compared groups across all categories, including an adjusted difference of -27 units (p = .50) for deployed versus nondeployed veterans and 87 units (p = .13) for veterans with versus without symptoms of GWVIs., Conclusions: Neither deployment to the Gulf nor symptoms compatible with GWVIs are associated with long-term serum AChE activity.

BackgroundHabitual alcohol use can be an indicator of alcohol dependence, which is associated with a wide range of serious health problems.MethodsWe completed a genome-wide association study in 126,936 European American and 17,029 African American subjects in the Veterans Affairs Million Veteran Program for a quantitative phenotype based on maximum habitual alcohol consumption.ResultsADH1B, on chromosome 4, was the lead locus for both populations: for the European American sample, rs1229984 (p = 4.9 × 10-47); for African American, rs2066702 (p = 2.3 × 10-12). In the European American sample, we identified three additional genome-wide-significant maximum habitual alcohol consumption loci: on chromosome 17, rs77804065 (p = 1.5 × 10-12), at CRHR1 (corticotropin-releasing hormone receptor 1); the protein product of this gene is involved in stress and immune responses; and on chromosomes 8 and 10. European American and African American samples were then meta-analyzed; the associated region at CRHR1 increased in significance to 1.02 × 10-13, and we identified two additional genome-wide significant loci, FGF14 (p = 9.86 × 10-9) (chromosome 13) and a locus on chromosome 11. Besides ADH1B, none of the five loci have prior genome-wide significant support. Post-genome-wide association study analysis identified genetic correlation to other alcohol-related traits, smoking-related traits, and many others. Replications were observed in UK Biobank data. Genetic correlation between maximum habitual alcohol consumption and alcohol dependence was 0.87 (p = 4.78 × 10-9). Enrichment for cell types included dopaminergic and gamma-aminobutyric acidergic neurons in midbrain, and pancreatic delta cells.ConclusionsThe present study supports five novel alcohol-use risk loci, with particularly strong statistical support for CRHR1. Additionally, we provide novel insight regarding the biology of harmful alcohol use.

Affecting an estimated 88 million Americans, prediabetes increases the risk for developing type 2 diabetes mellitus (T2DM), and independently, cardiovascular disease, retinopathy, nephropathy, and neuropathy. Nevertheless, little is known about the use of metformin for diabetes prevention among patients in the Veterans Health Administration, the largest integrated healthcare system in the U.S. This is a retrospective observational cohort study of the proportion of Veterans with incident prediabetes who were prescribed metformin at the Veterans Health Administration from October 2010 to September 2019. Among 1,059,605 Veterans with incident prediabetes, 12,009 (1.1%) were prescribed metformin during an average 3.4 years of observation after diagnosis. Metformin prescribing was marginally higher (1.6%) among those with body mass index (BMI) ≥35 kg/m2, age <60 years, HbA1c≥6.0%, or those with a history of gestational diabetes, all subgroups at a higher risk for progression to T2DM. In a multivariable model, metformin was more likely to be prescribed for those with BMI ≥35 kg/m2 incidence rate ratio [IRR] 2.6 [95% confidence intervals (CI): 2.1–3.3], female sex IRR, 2.4 [95% CI: 1.8–3.3], HbA1c≥6% IRR, 1.93 [95% CI: 1.5–2.4], age <60 years IRR, 1.7 [95% CI: 1.3–2.3], hypertriglyceridemia IRR, 1.5 [95% CI: 1.2–1.9], hypertension IRR, 1.5 [95% CI: 1.1–2.1], Major Depressive Disorder IRR, 1.5 [95% CI: 1.1–2.0], or schizophrenia IRR, 2.1 [95% CI: 1.2–3.8]. Over 20% of Veterans with prediabetes attended a comprehensive structured lifestyle modification clinic or program. Among Veterans with prediabetes, metformin was prescribed to 1.1% overall, a proportion that marginally increased to 1.6% in the subset of individuals at highest risk for progression to T2DM. [ABSTRACT FROM AUTHOR]

The course of posttraumatic stress disorder (PTSD) symptoms varies among veterans of war zones, but sources of variation in long‐term symptom course remain poorly understood. Modeling of symptom growth trajectories facilitates the understanding of predictors of individual outcomes over time. Although growth mixture modeling (GMM) has been applied to military populations, few studies have incorporated both predeployment and follow‐up measurements over an extended time. In this prospective study, 1,087 U.S. Army soldiers with varying military occupational specialties and geographic locations were assessed before and after deployment to the Iraq war zone, with long‐term follow‐up assessment occurring at least 5 years after return from deployment. The primary outcome variable was the PTSD Checklist–Civilian Version summary score. GMM yielded four latent profiles, characterized as primarily asymptomatic (n = 194, 17.8%); postdeployment worsening symptoms (n = 84, 7.7%); mild symptoms (n = 320, 29.4%); and preexisting, with a chronic postdeployment elevation of symptoms (n = 489, 45.0%). Regression models comparing the primarily asymptomatic class to the symptomatic classes revealed that chronic symptom classes were associated with higher degrees of stress exposure, less predeployment social support, military reservist or veteran status at the most recent assessment, and poorer predeployment visual memory, ORs = 0.98–2.90. PTSD symptom course varies considerably over time after military deployment and is associated with potentially modifiable biopsychosocial factors that occur early in its course in addition to exposures and military status. [ABSTRACT FROM AUTHOR]

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. 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. 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). 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. [ABSTRACT FROM AUTHOR]

Factors affecting acetylcholine-mediated neurotransmission have been proposed as possible explanations for physical and mental health symptoms among veterans of the 1990-1991 Gulf War. This study was designed to examine relationships of deployment to the Gulf, as well as symptoms after military service, with postdeployment activity of acetylcholinesterase (AChE) and related enzymes.The patient population included 488 veterans, originally from Iowa at enlistment, who served in the US military during August 1990 to July 1991. Demographic, military, and clinical characteristics were obtained from a population-based cohort study (in 1995-1996) and from a nested case-control study (in 1999-2002). Stored serum samples (from the 1999-2002 assessment) were analyzed for activity of AChE and related enzymes. These two data sources were merged, and multiple linear regression models estimated the association of deployment, stress (anxiety) or mood disorders, and symptoms compatible with Gulf War veterans' illnesses (GWVIs), with enzyme activity.Seventy-four percent (n = 361) of veterans had been deployed to the Gulf. At the time of evaluation, 23% (n = 113) of participants reported anxiety and 15% (n = 71) reported mood disorders; 49% (n = 171 of 347 eligible veterans) had symptoms of GWVIs, and the median AChE activity was 839 units. AChE activity was similar for compared groups across all categories, including an adjusted difference of -27 units (p = .50) for deployed versus nondeployed veterans and 87 units (p = .13) for veterans with versus without symptoms of GWVIs.Neither deployment to the Gulf nor symptoms compatible with GWVIs are associated with long-term serum AChE activity. [ABSTRACT FROM AUTHOR]

Background: Approximately 697,000 members of the U.S. Armed Forces were deployed to the Persian Gulf in support of the 1990–1991 Persian Gulf War (GW). Subsequently, many deployed and some non-deployed veterans developed a chronic multi-symptom illness, now named Gulf War Illness (GWI). This manuscript outlines the methods and rationale for studying the genomics of GWI within the Million Veteran Program (MVP), a VA-based national research program that has linked medical records, surveys, and genomic data, enabling genome-wide association studies (GWASs). Methods: MVP participants who served in the military during the GW era were contacted by mail and invited to participate in the GWI study. A structured health questionnaire, based on a previously tested instrument, was also included in the mailing. Data on deployment locations and exposures, symptoms associated with GWI, clinical diagnoses, personal habits, and health care utilization were collected. Self-reported data will be augmented with chart reviews and structured international classification of disease codes, to classify participants by GWI case status. We will develop a phenotyping algorithm, based on two commonly used case definitions, to determine GWI status, and then conduct a nested case-control GWAS. Genetic variants associated with GWI will be investigated, and gene–gene and gene–environment interactions studied. The genetic overlap of GWI with, and causative mechanisms linking this illness to, other health conditions and the effects of genomic regulatory mechanisms on GWI risk will also be explored. Conclusions: The proposed initial GWAS described in this report will investigate the genomic underpinnings of GWI with a large sample size and state-of-the-art genomic analyses and phenotyping. The data generated will provide a rich and expansive foundation on which to build additional analyses. [ABSTRACT FROM AUTHOR]

Background Suicide is a major problem in severe mental illness (SMI), with increased risk for lifetime suicidal ideation and behavior compounded in veterans. Previous research has suggested that genomic risk factors exist for suicidal ideation and behavior, and we examined the genomic correlates of suicidal ideation and behavior in 8,049 male and 1,290 female veterans with schizophrenia or bipolar disorder. Methods Data were collected previously on demographic, clinical, and functional status factors, as well as self-reported suicidal ideation and behavior assessed with the Columbia Suicide Severity Rating Scale (lifetime version). For this study, we defined an ideation and behavior as a single latent trait, excluding patients with non-suicidal self-injurious behavior. A customized Affymetrix Axiom Biobank array was used to obtain genotype data. After sample and variant quality control steps and ancestry inference, analyses included 657,459 SNPs and 4,012 European American samples (with 3,223 cases and 789 controls, which include 3,507 males and 505 females), as well as 2,651 African American samples (with 1,955 cases and 696 controls, which include 2,249 males and 402 females). The results were then filtered with the imputation quality score R2>0.8, MAF>0.01, and Hardy-Weinberg equilibrium test p-value >1 x 10–6; a GWAS p-value threshold of 5 x 10–8 was adopted as genome-wide statistical significance. We performed both SNP-based analysis and gene-based analysis (using the UTMOST approach that leverages eQTL information across tissues from the GTEx project). To investigate the genetic correlation between the ideation and behavior score in the combined sample and other complex traits, we applied GNOVA, a framework to estimate the genetic overlap of ideation and behavior scores in schizophrenia or bipolar samples with respect to 2,626 traits from the UK Biobank (UKB) and other GWAS results. FDR was used to correct for multiple testing, and a q value<0.05 was set as the threshold for statistical significance. Results For European American (EA) and African American (AA) ancestry patients, no SNP passed the 5 x 10–8 the genome wide statistical significance; 4 SNPs were significant at 10–6 for the EA group, and 8 SNPs for the AA group. Gene-level analysis (UTMOST) identified 5 genes (GAMT 1.74×10–11, FTL 1.84×10–11, DCTN4 2.97×10–9, IYVE1 4.38×10–9, IQCC 7.07×10–9) from the EA group with suicide tendency; several had previously-noted clinical significance. For the GNOVA results, 25 traits showed statistically significant correlation at 10–3, and three survived FDR correction: depression in the past 2 weeks, miserableness, and tenseness in the past 2 weeks. All of the 25 traits described a mood or physical condition, but none of the traits included schizophrenia or bipolar disorder. Discussion Genomic correlates of suicidal ideation and behavior relate to traits in the general population that are linked to physical illness, mood, or anxiety. These findings suggest a commonality of genomic risk factors for suicidal ideation and behavior across SMI and the general population. [ABSTRACT FROM AUTHOR]

B Methods: b We conducted a genome-wide association study (GWAS) on 175,553 participants in the MVP who completed a survey that included the PHQ2 (two questions about mood state within the past two weeks), had genomic data and were of genetically assigned European descent. The polygenic risk score software PRSice2 was used to identify individual common SNP genetic liability from polygenic risk scores for depression in the MVP sample and available PGC and UKB summary statistics. We observed positive genetic correlations between depression and neuroticism, insomnia, and smoking initiation and negative genetic correlation between depression and subjective well-being and intelligence. [Extracted from the article]

B Abstract: b Individuals vary in their liability to develop Posttraumatic Stress Disorder (PTSD), the symptoms of which are highly heterogeneous, following exposure to life-threatening trauma. Using genetic data from more than 250,000 participants in the Million Veteran Program, genome-wide association analyses were conducted using a validated electronic health record algorithmically defined PTSD diagnosis phenotype (48,221 cases and 217,223 controls), a self-reported PTSD diagnosis phenotype (43,085 cases and 203,681 controls), and PTSD quantitative symptom phenotypes (212,007 individuals). These results point to the utility of genetics to inform the biological coherence of the PTSD syndrome despite considerable heterogeneity at the symptom level, and to provide new directions for treatment development. [Extracted from the article]

B Abstract: b Objective: Suicide is a major problem in severe mental illness (SMI), with increased risk for lifetime suicidal ideation and behavior compounded in veterans. The results were then filtered with the imputation quality score R2>0.8, MAF>0.01, and Hardy-Weinberg equilibrium test p-value >1 × 10-6; a GWAS p-value threshold of 5 × 10-8 was adopted as genome-wide statistical significance. We performed both SNP-based analysis and gene-based analysis (using the UTMOST approach that leverages eQTL information across tissues from the GTEx project). [Extracted from the article]