Correlates of suicidal behaviors and genetic risk among United States veterans with schizophrenia or bipolar I disorder.

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.

The Million Veteran Program 1990-1991 Gulf War Era Survey: An Evaluation of Veteran Response, Characteristics, and Representativeness of the Gulf War Era 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.

Metformin prescription for U.S. veterans with prediabetes, 2010-2019.

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.

Correlates of suicidal behaviors and genetic risk among United States veterans with schizophrenia or bipolar I disorder.

Objective: 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 mental and physical health problems, prior pharmacological treatments, and aggregate genetic factors has potential to inform risk stratification and mitigation strategies. Methods: In this study of 3,942 SCZ and 5,414 BPI patients receiving VA care, self-reported SB and ideation were assessed using the Columbia Suicide Severity Rating Scale (C-SSRS). These cross-sectional data were integrated with electronic health records (EHR), and compared by lifetime diagnoses, treatment histories, follow-up screenings, and mortality data. Polygenic scores (PGS) for traits related to psychiatric disorders, substance use, and cognition were constructed using available genomic data, and exploratory genome-wide association studies were performed to identify and prioritize specific loci. Results: Only 20% of veterans who self-reported SB had a corroborating ICD-9/10 code in their EHR; and among those who denied prior behaviors, more than 20% reported new-onset SB at follow-up. SB were associated with a range of psychiatric and non-psychiatric diagnoses, and with treatment with specific classes of psychotropic medications (e.g., antidepressants, antipsychotics, etc.). PGS for externalizing behaviors, smoking, suicide attempt, and major depressive disorder were also associated with attempt and ideation. Conclusions: Among individuals with a diagnosed mental illness, a GWAS for SB did not yield any significant loci. Self-reported SB were strongly associated with clinical variables across several EHR domains. Overall, clinical and polygenic analyses point to sequelae of substance-use related behaviors and other psychiatric comorbidities as strong correlates of prior and subsequent SB. Nonetheless, past SB was frequently not documented in clinical settings, underscoring the value of regular screening based on direct, in-person assessments, especially among high-risk individuals.

Penetrance and Pleiotropy of Polygenic Risk Scores for Schizophrenia, Bipolar Disorder, and Depression Among Adults in the US Veterans Affairs Health Care System.

Importance: Serious mental illnesses, including schizophrenia, bipolar disorder, and depression, are heritable, highly multifactorial disorders and major causes of disability worldwide. Objective: To benchmark the penetrance of current neuropsychiatric polygenic risk scores (PRSs) in the Veterans Health Administration health care system and to explore associations between PRS and broad categories of human disease via phenome-wide association studies. Design, Setting, and Participants: Extensive Veterans Health Administration's electronic health records were assessed from October 1999 to January 2021, and an embedded cohort of 9378 individuals with confirmed diagnoses of schizophrenia or bipolar 1 disorder were found. The performance of schizophrenia, bipolar disorder, and major depression PRSs were compared in participants of African or European ancestry in the Million Veteran Program (approximately 400 000 individuals), and associations between PRSs and 1650 disease categories based on ICD-9/10 billing codes were explored. Last, genomic structural equation modeling was applied to derive novel PRSs indexing common and disorder-specific genetic factors. Analysis took place from January 2021 to January 2022. Main Outcomes and Measures: Diagnoses based on in-person structured clinical interviews were compared with ICD-9/10 billing codes. PRSs were constructed using summary statistics from genome-wide association studies of schizophrenia, bipolar disorder, and major depression. Results: Of 707 299 enrolled study participants, 459 667 were genotyped at the time of writing; 84 806 were of broadly African ancestry (mean [SD] age, 58 [12.1] years) and 314 909 were of broadly European ancestry (mean [SD] age, 66.4 [13.5] years). Among 9378 individuals with confirmed diagnoses of schizophrenia or bipolar 1 disorder, 8962 (95.6%) were correctly identified using ICD-9/10 codes (2 or more). Among those of European ancestry, PRSs were robustly associated with having received a diagnosis of schizophrenia (odds ratio [OR], 1.81 [95% CI, 1.76-1.87]; P < 10-257) or bipolar disorder (OR, 1.42 [95% CI, 1.39-1.44]; P < 10-295). Corresponding effect sizes in participants of African ancestry were considerably smaller for schizophrenia (OR, 1.35 [95% CI, 1.29-1.42]; P < 10-38) and bipolar disorder (OR, 1.16 [95% CI, 1.11-1.12]; P < 10-10). Neuropsychiatric PRSs were associated with increased risk for a range of psychiatric and physical health problems. Conclusions and Relevance: Using diagnoses confirmed by in-person structured clinical interviews and current neuropsychiatric PRSs, the validity of an electronic health records-based phenotyping approach in US veterans was demonstrated, highlighting the potential of PRSs for disentangling biological and mediated pleiotropy.

Association of Gulf War Illness with Characteristics in Deployed vs. Non-Deployed Gulf War Era Veterans in the Cooperative Studies Program 2006/Million Veteran Program 029 Cohort: A Cross-Sectional Analysis.

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.

Genomics of Gulf War Illness in U.S. Veterans Who Served during the 1990-1991 Persian Gulf War: Methods and Rationale for Veterans Affairs Cooperative Study #2006.

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.

Cooperative Studies Program (CSP) #572: A Study of Serious Mental Illness in Veterans as a Pathway to personalized medicine in Schizophrenia and Bipolar Illness.

BACKGROUND: Personalization of psychiatric treatment includes treatment of symptoms, cognition and functional deficits, suicide, and medical co-morbidities. VA Collaborative Study 572 examined a large sample of male and female veterans with schizophrenia (n=3,942) and with bipolar disorder (n=5,414) with phenotyping and genomic analyses. We present the results to date and future directions. METHODS: All veterans received a structured diagnostic interview and assessments of suicidal ideation and behavior, PTSD, and health. Veterans with schizophrenia were assessed for negative symptoms and lifetime depression. All were assessed with a cognitive and functional capacity assessment. Data for genome wide association studies were collected. Controls came from the VA Million Veteran Program. RESULTS: Suicidal ideation or behavior was present in 66%. Cognitive and functional deficits were consistent with previous studies. 40% of the veterans with schizophrenia had a lifetime major depressive episode and PTSD was present in over 30%. Polygenic risk score (PRS) analyses indicated that cognitive and functional deficits overlapped with PRS for cognition, education, and intelligence in the general population and PRS for suicidal ideation and behavior correlated with previous PRS for depression and suicidal ideation and behavior, as did the PRS for PTSD. DISCUSSION: Results to date provide directions for personalization of treatment in SMI, veterans with SMI, and veterans in general. The results of the genomic analyses suggest that cognitive deficits in SMI may be associated with general population features. Upcoming genomic analyses will reexamine the issues above, as well as genomic factors associated with smoking, substance abuse, negative symptoms, and treatment response.

Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions.

Major depressive disorder is the most common neuropsychiatric disorder, affecting 11% of veterans. Here we report results of a large meta-analysis of depression using data from the Million Veteran Program, 23andMe, UK Biobank and FinnGen, including individuals of European ancestry (n = 1,154,267; 340,591 cases) and African ancestry (n = 59,600; 25,843 cases). Transcriptome-wide association study analyses revealed significant associations with expression of NEGR1 in the hypothalamus and DRD2 in the nucleus accumbens, among others. We fine-mapped 178 genomic risk loci, and we identified likely pathogenicity in these variants and overlapping gene expression for 17 genes from our transcriptome-wide association study, including TRAF3. Finally, we were able to show substantial replications of our findings in a large independent cohort (n = 1,342,778) provided by 23andMe. This study sheds light on the genetic architecture of depression and provides new insight into the interrelatedness of complex psychiatric traits.

Vascular Patterning as Integrative Readout of Complex Molecular and Physiological Signaling by VESsel GENeration Analysis.

The molecular signaling cascades that regulate angiogenesis and microvascular remodeling are fundamental to normal development, healthy physiology, and pathologies such as inflammation and cancer. Yet quantifying such complex, fractally branching vascular patterns remains difficult. We review application of NASA's globally available, freely downloadable VESsel GENeration (VESGEN) Analysis software to numerous examples of 2D vascular trees, networks, and tree-network composites. Upon input of a binary vascular image, automated output includes informative vascular maps and quantification of parameters such as tortuosity, fractal dimension, vessel diameter, area, length, number, and branch point. Previous research has demonstrated that cytokines and therapeutics such as vascular endothelial growth factor, basic fibroblast growth factor (fibroblast growth factor-2), transforming growth factor-beta-1, and steroid triamcinolone acetonide specify unique "fingerprint" or "biomarker" vascular patterns that integrate dominant signaling with physiological response. In vivo experimental examples described here include vascular response to keratinocyte growth factor, a novel vessel tortuosity factor; angiogenic inhibition in humanized tumor xenografts by the anti-angiogenesis drug leronlimab; intestinal vascular inflammation with probiotic protection by Saccharomyces boulardii, and a workflow programming of vascular architecture for 3D bioprinting of regenerative tissues from 2D images. Microvascular remodeling in the human retina is described for astronaut risks in microgravity, vessel tortuosity in diabetic retinopathy, and venous occlusive disease.

Genome-wide association analyses of post-traumatic stress disorder and its symptom subdomains in the Million Veteran Program.

We conducted genome-wide association analyses of over 250,000 participants of European (EUR) and African (AFR) ancestry from the Million Veteran Program using electronic health record-validated post-traumatic stress disorder (PTSD) diagnosis and quantitative symptom phenotypes. Applying genome-wide multiple testing correction, we identified three significant loci in European case-control analyses and 15 loci in quantitative symptom analyses. Genomic structural equation modeling indicated tight coherence of a PTSD symptom factor that shares genetic variance with a distinct internalizing (mood-anxiety-neuroticism) factor. Partitioned heritability indicated enrichment in several cortical and subcortical regions, and imputed genetically regulated gene expression in these regions was used to identify potential drug repositioning candidates. These results validate the biological coherence of the PTSD syndrome, inform its relationship to comorbid anxiety and depressive disorders and provide new considerations for treatment.

Genome-Wide Association Studies of Schizophrenia and Bipolar Disorder in a Diverse Cohort of US Veterans.

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.

Suicidal ideation, behavior, and mortality in male and female US veterans with severe mental illness.

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.

Reproducible Genetic Risk Loci for Anxiety: Results From ∼200,000 Participants in the Million Veteran Program.

OBJECTIVE: Anxiety disorders are common and often disabling. The goal of this study was to examine the genetic architecture of anxiety disorders and anxiety symptoms, which are also frequently comorbid with other mental disorders, such as major depressive disorder. METHODS: Using one of the world's largest biobanks including genetic, environmental, and medical information, the Million Veteran Program, the authors performed a genome-wide association study (GWAS) of a continuous trait for anxiety (based on score on the Generalized Anxiety Disorder 2-item scale [GAD-2], N=199,611) as the primary analysis and self-report of physician diagnosis of anxiety disorder (N=224,330) as a secondary analysis. RESULTS: The authors identified five genome-wide significant signals for European Americans and one for African Americans on GAD-2 score. The strongest were on chromosome 3 (rs4603973) near SATB1, a global regulator of gene expression, and on chromosome 6 (rs6557168) near ESR1, which encodes an estrogen receptor. The locus identified on chromosome 7 (rs56226325, MAF=0.17) near MAD1L1 was previously identified in GWASs of bipolar disorder and schizophrenia. The authors replicated these findings in the summary statistics of two major published GWASs for anxiety, and also found evidence of significant genetic correlation between the GAD-2 score results and previous GWASs for anxiety (rg=0.75), depression (rg=0.81), and neuroticism (rg=0.75). CONCLUSIONS: This is the largest GWAS of anxiety traits to date. The authors identified novel genome-wide significant associations near genes involved with global regulation of gene expression (SATB1) and the estrogen receptor alpha (ESR1). Additionally, the authors identified a locus (MAD1L1) that may have implications for genetic vulnerability across several psychiatric disorders. This work provides new insights into genetic risk mechanisms underpinning anxiety and related psychiatric disorders.

Genome-wide association study of post-traumatic stress disorder reexperiencing symptoms in >165,000 US veterans.

Post-traumatic stress disorder (PTSD) is a major problem among military veterans and civilians alike, yet its pathophysiology remains poorly understood. We performed a genome-wide association study and bioinformatic analyses, which included 146,660 European Americans and 19,983 African Americans in the US Million Veteran Program, to identify genetic risk factors relevant to intrusive reexperiencing of trauma, which is the most characteristic symptom cluster of PTSD. In European Americans, eight distinct significant regions were identified. Three regions had values of P < 5 × 10-10: CAMKV; chromosome 17 closest to KANSL1, but within a large high linkage disequilibrium region that also includes CRHR1; and TCF4. Associations were enriched with respect to the transcriptomic profiles of striatal medium spiny neurons. No significant associations were observed in the African American cohort of the sample. Results in European Americans were replicated in the UK Biobank data. These results provide new insights into the biology of PTSD in a well-powered genome-wide association study.

Genome-wide Association Study of Maximum Habitual Alcohol Intake in >140,000 U.S. European and African American Veterans Yields Novel Risk Loci.

BACKGROUND: Habitual alcohol use can be an indicator of alcohol dependence, which is associated with a wide range of serious health problems. METHODS: We 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. RESULTS: ADH1B, 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. CONCLUSIONS: The 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.

Validation of an Electronic Medical Record-Based Algorithm for Identifying Posttraumatic Stress Disorder in U.S. Veterans.

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.

Spanish Abstracts by Asociación Chilena de Estrés Traumático (ACET) Validación de un algoritmo basado en registros médicos electrónicos para identificar el trastorno por estrés postraumático en veteranos de los EE. UU. VALIDACIÓN DE ALGORITOMO DE TEPT Desarrollamos un algoritmo para identificar a los veteranos de EE. UU. con historial de trastorno de estrés postraumático (TEPT), utilizando el sistema de registro médico electrónico (RME) del Departamento de Asuntos de Veteranos (AS). Este trabajo fue motivado por la necesidad de crear un fenotipo válido, basado en RME para identificar miles de casos y controles para un estudio de asociación del genoma del TEPT en los veteranos. Utilizamos la revisión manual de tablas (n = 500) como gold estándar. Tanto para el algoritmo como para la revisión de la tabla, fueron posibles tres clasificaciones: PTSD probable, PTSD posible y probablemente no PTSD. Usamos la regresión Lasso con validación cruzada para seleccionar los factores de pronóstico estadísticamente significativos del TEPT a partir de la RME y luego generar una puntuación de probabilidad pronosticada de ser un caso de TEPT para cada participante en la población del estudio (rango: 0-1.00). Comparando el rendimiento de nuestro enfoque probabilístico (algoritmo Lasso) con un enfoque basado en reglas (algoritmo de Clasificación Internacional de Enfermedades [CIE]), el algoritmo Lasso mostró un porcentaje de acuerdo global modestamente más alto con la revisión de tablas que el algoritmo CIE (80% vs. 75). %), mayor sensibilidad (0.95 frente a 0.84) y mayor precisión (AUC = 0.95 frente a 0.90). Aplicamos un punto de corte de probabilidad de 0.7 a los resultados de Lasso para determinar el estado final de control de caso de TEPT para la población de AV. El algoritmo final tuvo una sensibilidad de 0.99, una especificidad de 0.99, un valor predictivo positivo de 0.95 y un valor predictivo negativo de 1.00 para la clasificación de TEPT (agrupación de TEPT posible y probablemente no TEPT) según lo determinado por la revisión de la tabla. Este algoritmo puede ser útil para otros esfuerzos de investigación y mejora de la calidad dentro del AV.

Genomics of posttraumatic stress disorder in veterans: Methods and rationale for Veterans Affairs Cooperative Study #575B.

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.

Group Battlefield Acupuncture in Primary Care for Veterans with Pain.

OBJECTIVE: To obtain preliminary data on the short- and intermediate-term effects of battlefield acupuncture (BFA) on self-reported pain intensity in a relatively large cohort of veterans to assess whether a more comprehensive clinical trial evaluation is warranted. METHODS: The treatment, in an outpatient group setting, consisted of up to five auricular semipermanent needles inserted into each ear at prespecified points. Efficacy of treatment was measured by self-reported pain, using the Defense and Veterans Pain Rating Scale, just before treatment and at posttreatment days 0, 1, 7, and 30. RESULTS: A total of 112 patients attended the group clinics. The mean pretreatment pain score was 6.8, with an immediate postprocedure decrease of 2.4 points. The proportion of patients reporting decreased pain was 88.4%, 80.7%, 52.4%, and 51% at posttreatment days 0, 1, 7, and 30, respectively. CONCLUSIONS: The short- and intermediate-term beneficial effect of BFA on chronic pain is clinically meaningful. The large proportion of patients reporting decreased pain even 30 days after treatment suggests that the long-term effect of BFA merits further investigation.