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Cases for a disease can be defined broadly using diagnostic codes, or narrowly using gold-standard confirmation that often is not available in large administrative datasets. These different definitions can have significant impacts on the results and conclusions of studies. We conducted this study to assess how using melanoma phecodes versus histologic confirmation for invasive or in situ melanoma impacts the results of a genome-wide association study (GWAS) using the Million Veteran Program. Melanoma status was determined three ways: (1) by the presence of two or more phecodes, (2) histologically-confirmed invasive melanoma, and (3) histologically-confirmed melanoma in situ. We conducted a GWAS for variants with minor allele frequencies of 1% or greater. There were 45,665 cases in the phecode cohort, 5364 cases in the confirmed invasive melanoma cohort, and 4792 cases in the confirmed melanoma in situ cohort. There were 20,457 variants significant at the genome-wide level in the phecode cohort, 2582 in the invasive melanoma cohort, and 1989 in the melanoma in situ cohort. Most of the variants identified in the phecode cohort did not replicate in the histologically-confirmed cohorts. The different case definitions led to large differences in sample size and variants associated at the genome-wide level. Unvalidated and imprecise case definitions can lead to less accurate results. Investigators should use validated phenotypes when gold-standard definitions are not available., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2025. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: As a mega-biobank linked to a national healthcare system, the Million Veteran Program (MVP) can directly improve the health care of participants. To determine the feasibility and outcomes of returning medically actionable genetic results to MVP participants, the program launched the MVP Return of Actionable Results (MVP-ROAR) Study, with familial hypercholesterolemia (FH) as an exemplar actionable condition., Methods: The MVP-ROAR Study consists of a completed single-arm pilot phase and an ongoing randomized clinical trial (RCT), in which MVP participants are recontacted and invited to receive clinical confirmatory gene sequencing testing and a telegenetic counseling intervention. The primary outcome of the RCT is 6-month change in low-density lipoprotein cholesterol (LDL-C) between participants receiving results at baseline and those receiving results after 6 months., Results: The pilot developed processes to identify and recontact participants nationally with probable pathogenic variants in low-density lipoprotein receptor (LDLR) on the MVP genotype array, invite them to clinical confirmatory gene sequencing, and deliver a telegenetic counseling intervention. Among participants in the pilot phase, 8 (100%) had active statin prescriptions after 6 months. Results were shared with 16 first-degree family members. Six-month ΔLDL-C (low-density lipoprotein cholesterol) after the genetic counseling intervention was -37 mg/dL (95% CI: -12 to -61; P = .03). The ongoing RCT will determine between-arm differences in this primary outcome., Conclusion: While underscoring the importance of clinical confirmation of research results, the pilot phase of the MVP-ROAR Study marks a turning point in MVP and demonstrates the feasibility of returning genetic results to participants and their providers. The ongoing RCT will contribute to understanding how such a program might improve patient health care and outcomes., Clinical Trial Registration: ClinicalTrials.gov ID NCT04178122., (Published by Elsevier Inc.)

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.)

One of the justifiable criticisms of human genetic studies is the underrepresentation of participants from diverse populations. Lack of inclusion must be addressed at-scale to identify causal disease factors and understand the genetic causes of health disparities. We present genome-wide associations for 2068 traits from 635,969 participants in the Department of Veterans Affairs Million Veteran Program, a longitudinal study of diverse United States Veterans. Systematic analysis revealed 13,672 genomic risk loci; 1608 were only significant after including non-European populations. Fine-mapping identified causal variants at 6318 signals across 613 traits. One-third ( n = 2069) were identified in participants from non-European populations. This reveals a broadly similar genetic architecture across populations, highlights genetic insights gained from underrepresented groups, and presents an extensive atlas of genetic associations.

Importance: Non-Hispanic Black (hereafter, Black) individuals experience worse prostate cancer outcomes due to socioeconomic and racial inequities of access to care. Few studies have empirically evaluated these disparities across different health care systems., Objective: To describe the racial and ethnic and neighborhood socioeconomic status (nSES) disparities among residents of the same communities who receive prostate cancer care in the US Department of Veterans Affairs (VA) health care system vs other settings., Design, Setting, and Participants: This cohort study obtained data from the VA Central Cancer Registry for veterans with prostate cancer who received care within the VA Greater Los Angeles Healthcare System (VA cohort) and from the California Cancer Registry (CCR) for nonveterans who received care outside the VA setting (CCR cohort). The cohorts consisted of all males with incident prostate cancer who were living within the same US Census tracts. These individuals received care between 2000 and 2018 and were followed up until death from any cause or censoring on December 31, 2018. Data analyses were conducted between September 2022 and December 2023., Exposures: Health care setting, self-identified race and ethnicity (SIRE), and nSES., Main Outcomes and Measures: The primary outcome was all-cause mortality (ACM). Cox proportional hazards regression models were used to estimate hazard ratios for associations of SIRE and nSES with prostate cancer outcomes in the VA and CCR cohorts., Results: Included in the analysis were 49 461 males with prostate cancer. Of these, 1881 males were in the VA cohort (mean [SD] age, 65.3 [7.7] years; 833 Black individuals [44.3%], 694 non-Hispanic White [hereafter, White] individuals [36.9%], and 354 individuals [18.8%] of other or unknown race). A total of 47 580 individuals were in the CCR cohort (mean [SD] age, 67.0 [9.6] years; 8183 Black individuals [17.2%], 26 206 White individuals [55.1%], and 13 191 individuals [27.8%] of other or unknown race). In the VA cohort, there were no racial disparities observed for metastasis, ACM, or prostate cancer-specific mortality (PCSM). However, in the CCR cohort, the racial disparities were observed for metastasis (adjusted odds ratio [AOR], 1.36; 95% CI, 1.22-1.52), ACM (adjusted hazard ratio [AHR], 1.13; 95% CI, 1.04-1.24), and PCSM (AHR, 1.15; 95% CI, 1.05-1.25). Heterogeneity was observed for the racial disparity in ACM in the VA vs CCR cohorts (AHR, 0.90 [95% CI, 0.76-1.06] vs 1.13 [95% CI, 1.04-1.24]; P = .01). No evidence of nSES disparities was observed for any prostate cancer outcomes in the VA cohort. However, in the CCR cohort, heterogeneity was observed for nSES disparities with ACM (AHR, 0.82; 95% CI, 0.80-0.84; P = .002) and PCSM (AHR, 0.86; 95% CI, 0.82-0.89; P = .007)., Conclusions and Relevance: Results of this study suggest that racial and nSES disparities were wider among patients seeking care outside of the VA health care system. Health systems-related interventions that address access barriers may mitigate racial and socioeconomic disparities in prostate cancer.

Background: The risk factors associated with the stages of Coronavirus Disease-2019 (COVID-19) disease progression are not well known. We aim to identify risk factors specific to each state of COVID-19 progression from SARS-CoV-2 infection through death., Methods and Results: We included 648,202 participants from the Veteran Affairs Million Veteran Program (2011-). We identified characteristics and 1,809 ICD code-based phenotypes from the electronic health record. We used logistic regression to examine the association of age, sex, body mass index (BMI), race, and prevalent phenotypes to the stages of COVID-19 disease progression: infection, hospitalization, intensive care unit (ICU) admission, and 30-day mortality (separate models for each). Models were adjusted for age, sex, race, ethnicity, number of visit months and ICD codes, state infection rate and controlled for multiple testing using false discovery rate (≤0.1). As of August 10, 2020, 5,929 individuals were SARS-CoV-2 positive and among those, 1,463 (25%) were hospitalized, 579 (10%) were in ICU, and 398 (7%) died. We observed a lower risk in women vs. men for ICU and mortality (Odds Ratio (95% CI): 0.48 (0.30-0.76) and 0.59 (0.31-1.15), respectively) and a higher risk in Black vs. Other race patients for hospitalization and ICU (OR (95%CI): 1.53 (1.32-1.77) and 1.63 (1.32-2.02), respectively). We observed an increased risk of all COVID-19 disease states with older age and BMI ≥35 vs. 20-24 kg/m2. Renal failure, respiratory failure, morbid obesity, acid-base balance disorder, white blood cell diseases, hydronephrosis and bacterial infections were associated with an increased risk of ICU admissions; sepsis, chronic skin ulcers, acid-base balance disorder and acidosis were associated with mortality., Conclusions: Older age, higher BMI, males and patients with a history of respiratory, kidney, bacterial or metabolic comorbidities experienced greater COVID-19 severity. Future studies to investigate the underlying mechanisms associated with these phenotype clusters and COVID-19 are warranted., Competing Interests: The authors have declared that no competing interests exist.

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.)

Cognitive impairment is a frequent and serious problem in patients with various forms of severe mental illnesses (SMI), including schizophrenia (SZ) and bipolar disorder (BP). Recent research suggests genetic links to several cognitive phenotypes in both SMI and in the general population. Our goal in this study was to identify potential genomic signatures of cognitive functioning in veterans with severe mental illness and compare them to previous findings for cognition across different populations. Veterans Affairs (VA) Cooperative Studies Program (CSP) Study #572 evaluated cognitive and functional capacity measures among SZ and BP patients. In conjunction with the VA Million Veteran Program, 3,959 European American (1,095 SZ, 2,864 BP) and 2,601 African American (1,095 SZ, 2,864 BP) patients were genotyped using a custom Affymetrix Axiom Biobank array. We performed a genome-wide association study of global cognitive functioning, constructed polygenic scores for SZ and cognition in the general population, and examined genetic correlations with 2,626 UK Biobank traits. Although no single locus attained genome-wide significance, observed allelic effects were strongly consistent with previous studies. We observed robust associations between global cognitive functioning and polygenic scores for cognitive performance, intelligence, and SZ risk. We also identified significant genetic correlations with several cognition-related traits in UK Biobank. In a diverse cohort of U.S. veterans with SZ or BP, we demonstrate broad overlap of common genetic effects on cognition in the general population, and find that greater polygenic loading for SZ risk is associated with poorer cognitive performance., (Published 2019. This article is a U.S. Government work and is in the public domain in the USA.)

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., (Copyright © 2019. Published by Elsevier Inc.)

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.

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.)

Background: Familial hypercholesterolemia (FH) is characterized by inherited high levels of low-density lipoprotein cholesterol (LDL-C) and premature coronary heart disease (CHD). Over a thousand low-frequency variants in LDLR, APOB and PCSK9 have been implicated in FH but few have been examined at the population level. We aim to estimate the phenotypic effects of a subset of FH variants on LDL-C and clinical outcomes among 331,107 multi-ethnic participants., Methods: We examined the individual and collective association between putatively pathogenic FH variants included on the MVP biobank array and the maximum LDL-C level over an interval of 15 years (maxLDL). We assessed the collective effect on clinical outcomes by leveraging data from 61.7 million clinical encounters., Results: We found 8 out of 16 putatively pathogenic FH variants with ≥30 observed carriers to be significantly associated with elevated maxLDL (9.4-80.2 mg/dL). Phenotypic effects were similar for European and African Americans despite substantial differences in carrier frequencies. Based on observed effects on maxLDL, we identified a total of 748 carriers (1:443) who had elevated maxLDL (36.5±1.4 mg/dL, p=1.2×10 -152 ), and higher prevalence of clinical diagnoses related to hypercholesterolemia and CHD in a phenome-wide scan. Adjusted for maxLDL, FH variants collectively associated with higher prevalence of CHD (odds ratio, 1.59 [95% CI 1.36-1.86], p=1.1×10 -8 ) but not peripheral artery disease., Conclusions: The distribution and phenotypic effects of putatively pathogenic FH variants were heterogeneous within and across variants. More robust evidence of genotype-phenotype associations of FH variants in multi-ethnic populations is needed to accurately infer at-risk individuals from genetic screening.

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.)