Gulf War Illness (GWI) is a multi-symptom chronic condition that affects Veterans who served in the 1990–1991 Gulf War (GW). To generate novel information about GWI pathogenesis, we used genome-wide data available from 33 523 Veterans of diverse ancestral backgrounds who served during the 1990–1991 Gulf War era (34% deployed). Polygenic score (PGS) analysis showed GWI pleiotropy for several traits with the strongest evidence for type-2 diabetes (T2D), anxiety, and depression. While T2D PGS was associated with higher GWI odds in GW Veterans, anxiety and depression PGSs were associated with higher odds of GWI in non-deployed GW-era Veterans. Seven independent variants were identified (P < 5 × 10-8). Two of them were supported by independent transcriptomic and phenome-wide analyses. Rs4675853 was associated with AGXT, MAB21L4, and ATG4Btranscriptomic regulation and with sex hormone-binding globulin levels. Rs138168412 was associated with AOPEPtranscriptomic regulation and with respiratory function and physical strength. The TWAS identified five additional loci such as CEMIPin the cerebellum and SNCGin the adrenal gland. The results provide a comprehensive assessment of the polygenic architecture of GWI research definitions, identifying mechanisms potentially relevant to the disease pathogenesis.

Background:Understanding associations between diet and long-term risk for colorectal cancer (CRC) among US veterans may provide insight for patient-clinician decisions about lifestyle recommendations as part of a CRC screening program. Methods:Asymptomatic US veterans aged 50 to 75 years who received screening colonoscopy between 1994 and 1997 were followed through 2009. The most significant colonoscopy findings (MSCFs) across the study period were classified as no neoplasia, not advanced adenomas, or advanced neoplasia (AN). The food frequency questionnaire was used to calculate raw and percent scores for the Healthy Eating Index (HEI), Mediterranean diet (MD), and Dietary Approaches to Stop Hypertension (DASH) dietary patterns. In cross-sectional analyses, multinomial logistic regression models tested for associations between dietary pattern scores and MSCF, controlling for demographics. Results:Among 3023 participants with complete data, 96.7% were male, and 83.8% were non-Hispanic White. Higher dietary patterns scores (ie, healthier diet) had similar or lower adjusted odds ratios (aORs) for AN vs no neoplasia (HEI: aOR, 1.00 [95% CI, 0.99-1.01]; MD: aOR, 0.95 [95% CI, 0.90-1.00]; DASH: aOR, 0.99 [95% CI, 0.98-1.00]). Higher grain category scores generally had lower aORs for AN for each dietary pattern (HEI: aOR, 0.96 [95% CI, 0.93-0.99]; MD: aOR, 0.29 [95% CI, 0.14-0.62]; DASH: aOR, 0.86 [95% CI, 0.78-0.95]). Conclusions:Healthy dietary patterns were associated with lower aORs for colonic neoplasia among veterans enrolled in a CRC screening program. More research is needed to determine the role of dietary assessments for tailored CRC prevention and surveillance.

Understanding how exercise improves whole-body insulin sensitivity (Si) involves complex molecular signaling. This study examines skeletal muscle gene expression changes related to Si, considering sex differences, exercise amount, and intensity to identify pharmacologic targets mimicking exercise benefits. Fifty-three participants from STRRIDE (Studies of Targeted Risk Reduction Interventions through Defined Exercise) I and II completed eight months of aerobic training. Gene expression was assessed via Affymetrix and Illumina technologies, and Si was measured using intravenous glucose tolerance tests. A novel discovery protocol integrating literature-derived and data-driven modeling identified causal pathways and direct transcriptional targets. In women, exercise amount primarily influenced transcription factor targets, which were generally inhibitory, while in men, exercise intensity drove activating targets. Common transcription factors included ATF1, CEBPA, BACH2, and STAT1. Si-related transcriptional targets included TACR3 and TMC7 for intensity-driven effects, and GRIN3B and EIF3B for amount-driven effects. Two key pathways mediating Si improvements were identified: estrogen signaling and protein kinase C (PKC) signaling, both converging on the epidermal growth factor receptor (EGFR) and other relevant targets. The molecular pathways underlying Si improvements varied by sex and exercise parameters, highlighting potential skeletal muscle-specific drug targets such as EGFR to replicate the metabolic benefits of exercise.

Suicidal thoughts and behaviors originate from heterogeneous mechanisms, including behavioral disinhibition characteristic of "externalizing" disorders (e.g., substance use disorders, antisocial personality disorder, etc.). Prior work has demonstrated strong genetic overlap between externalizing and suicide attempts. In the current analysis, we investigate the co-occurrence between a broader array of suicide phenotypes (i.e., suicide deaths, non-fatal attempts, suicidal ideation) and the externalizing spectrum using data from the Million Veteran Program (MVP) Cohort. We leverage the large-scale MVP database to (1) estimate a latent genomic factor for externalizing comprised of MVP data (MVP-EXT) using genomic structural equation modeling (GenomicSEM), (2) validate these results against prior externalizing models and other traits, (3) examine the genetic overlap between externalizing and suicide outcomes using multiple approaches (e.g., genetic correlations, polygenic scores, and post mortem brain tissue of suicide deaths), and (4) explore whether phenotypic externalizing is prospectively associated with death by suicide. We identify 155 loci in our meta-analysis of European-like (EUR-like, N = 310,498) and African-like (AFR-like, N = 99,949) MVP participants. MVP-EXT showed a strong genetic correlation with a prior, non-MVP externalizing factor (rG = 0.87, 95% CI = 0.83, 0.91) and suicide attempt in both EUR-like (rG = 0.67, 95% CI = 0.60, 0.74) and AFR-like (rG = 0.62, 95% CI = 0.42, 0.81) veterans. MVP-EXT polygenic scores were associated with suicidal ideation (OR = 1.09, 95% CI = 1.05, 1.13) and suicide attempts (OR = 1.20, 95% CI = 1.13, 1.27) in independent cohorts. MVP-EXT associated genes showed significant enrichment particularly within inhibitory neurons in suicide deaths compared to deaths from other causes. A phenotypic score for externalizing was prospectively associated with death by suicide in MVP (HR = 1.39, 95% CI = 1.33, 1.45). In total, our results reiterate that, while the relation between suicide with internalizing disorders has generally received more attention, externalizing is an important risk factor for suicide related behaviors. Greater attention should be paid to these problems as potential antecedents of suicide-related behaviors.

BACKGROUND:Accelerated transcriptomic and/or epigenetic age have been proposed as biomarkers of disrupted systemic health and of increased sensitivity to environmental exposures. Previously, we observed epigenetic age acceleration as a biomarker of sensitivity to air pollution, especially for traffic-related air pollution (TRAP) in urban cohorts. METHODS:Using 1024 participants from the CATHGEN cohort, we evaluated whether increased cardiovascular risk associated with TRAP was modified by transcriptomic aging. Residential proximity to major roadways was the measure of TRAP and peripheral arterial disease (PAD) and blood pressure were outcomes. Blood-based gene expression-based age acceleration (GEXAge AAD) and Horvath epigenetic age acceleration (DNAmAge AAD) were measures of age acceleration, and models were adjusted for chronological age, race, sex, smoking, socioeconomic status, body mass index, hyperlipidemia, and diabetes. RESULTS:We observed significant interactions between TRAP and GEXAge AAD and DNAmAge AAD, but these interactions were weaker than in previous analyses including only urban communities. Constraining the cohort to those residing in more urban environments strengthened the interaction between GEXAge AAD and TRAP. Interactions indicated that increased transcriptomic or epigenetic age elevated associations between proximity to roadways and PAD; the strongest interactions were identified in individuals with both accelerated epigenetic and transcriptomic age. Exploratory sex-stratified analyses identified potentially stronger associations in males, but these results would require further validation in larger studies. CONCLUSION:Similar to epigenetic age, elevated transcriptomic age may be an indicator of increased TRAP sensitivity. Individuals with jointly elevated epigenetic and transcriptomic age may have greater environmental health risks than those with elevated transcriptomic age alone.

BACKGROUND:Understanding the causal pathways, systems, and mechanisms through which exercise impacts human health is complex. This study explores molecular signaling related to whole-body insulin sensitivity (Si) by examining changes in skeletal muscle gene expression. The analysis considers differences by biological sex, exercise amount, and exercise intensity to identify potential molecular targets for developing pharmacologic agents that replicate the health benefits of exercise. METHODS:The study involved 53 participants from the STRRIDE I and II trials who completed eight months of aerobic training. Skeletal muscle gene expression was measured using Affymetrix and Illumina technologies, while pre- and post-training Si was assessed via an intravenous glucose tolerance test. A novel gene discovery protocol, integrating three literature-derived and data-driven modeling strategies, was employed to identify causal pathways and direct causal factors based on differentially expressed transcripts associated with exercise intensity and amount. RESULTS:In women, the transcription factor targets identified were primarily influenced by exercise amount and were generally inhibitory. In contrast, in men, these targets were driven by exercise intensity and were generally activating. Transcription factors such as ATF1, CEBPA, BACH2, and STAT1 were commonly activating in both sexes. Specific transcriptional targets related to exercise-induced Si improvements included TACR3 and TMC7 for intensity-driven effects, and GRIN3B and EIF3B for amount-driven effects. Two key signaling pathways mediating aerobic exercise-induced Si improvements were identified: one centered on estrogen signaling and the other on phorbol ester (PKC) signaling, both converging on the epidermal growth factor receptor (EGFR) and other relevant targets. CONCLUSIONS:The signaling pathways mediating Si improvements from aerobic exercise differed by sex and were further distinguished by exercise intensity and amount. Transcriptional adaptations in skeletal muscle related to Si improvements appear to be causally linked to estrogen and PKC signaling, with EGFR and other identified targets emerging as potential skeletal muscle-specific drug targets to mimic the beneficial effects of exercise on Si.

Research into aging has grown substantially with the creation of molecular biomarkers of biological age that can be used to determine age acceleration. Concurrently, nuclear magnetic resonance (NMR) assessment of biomarkers of inflammation and metabolism provides researchers with new ways to examine intermediate risk factors for chronic disease. We used data from a cardiac catheterization cohort to examine associations between biomarkers of cardiometabolic health and accelerated aging assessed using both gene expression (Transcriptomic Age) and DNA methylation (Hannum Age, GrimAge, Horvath Age, and Phenotypic Age). Linear regression models were used to associate accelerated aging with each outcome (cardiometabolic health biomarkers) while adjusting for chronological age, sex, race, and neighborhood socioeconomic status. Our study shows a robust association between GlycA and GrimAge (5.71, 95% CI = 4.36, 7.05, P = 7.94 x 10(-16)), Hannum Age (1.81, 95% CI = 0.65, 2.98, P = 2.30 x 10(-3)), and Phenotypic Age (2.88, 95% CI = 1.91, 3.87, P = 1.21 x 10(-8)). We also saw inverse associations between apolipoprotein A-1 and aging biomarkers. These associations provide insight into the relationship between aging and cardiometabolic health that may be informative for vulnerable populations.

BACKGROUND AND AIMS: Colorectal cancer (CRC) polygenic risk scores (PRS) may help personalize CRC prevention strategies. We investigated whether an existing PRS was associated with advanced neoplasia (AN) in a population undergoing screening and follow-up colonoscopy. METHODS: We evaluated 10-year outcomes in the Cooperative Studies Program #380 screening colonoscopy cohort, which includes a biorepository of selected individuals with baseline AN (defined as CRC or adenoma >= 10 mm or villous histology, or high-grade dysplasia) and matched individuals without AN. A PRS was constructed from 136 pre- specified CRC-risk single nucleotide polymorphisms. Multivariate logistic regression was used to evaluate the PRS for associations with AN prevalence at baseline screening colonoscopy or incident AN in participants with at least one follow-up colonoscopy. RESULTS: The PRS was associated with AN risk at baseline screening colonoscopy (P = .004). Participants in the lowest PRS quintile had more than a 70% decreased risk of AN at baseline (odds ratio 0.29, 95% confidence interval 0.14-0.58; P < .001) compared to participants with a PRS in the middle quintile. Using a PRS cut-off of more than the first quintile to indicate need for colonoscopy as primary screening, the sensitivity for detecting AN at baseline is 91.8%. We did not observe a relationship between the PRS and incident AN during follow-up (P = .28). CONCLUSION: A PRS could identify individuals at low risk for prevalent AN. Ongoing work will determine whether this PRS can identify a subset of individuals at sufficiently low risk who could safely delay or be reassured about noninvasive screening. Otherwise, more research is needed to augment these genetic tools to predict incident AN during long-term follow-up.

BACKGROUND:Despite the benefits of exercise, many individuals are unable or unwilling to adopt an exercise intervention. PURPOSE:The purpose of this analysis was to identify putative genetic variants associated with dropout from exercise training interventions among individuals in the STRRIDE trials. METHODS:We used a genome-wide association study approach to identify genetic variants in 603 participants initiating a supervised exercise intervention. Exercise intervention dropout occurred when a subject withdrew from further participation in the study or was otherwise lost to follow-up. RESULTS:Exercise intervention dropout was associated with a cluster of single-nucleotide polymorphisms with the top candidate being rs722069 (T/C, risk allele = C) (unadjusted p = 2.2 × 10-7, odds ratio = 2.23) contained within a linkage disequilibrium block on chromosome 16. In Genotype-Tissue Expression, rs722069 is an expression quantitative trait locus of the EARS2, COG7, and DCTN5 genes in skeletal muscle tissue. In subsets of the STRRIDE genetic cohort with available muscle gene expression (n = 37) and metabolic data (n = 82), at baseline the C allele was associated with lesser muscle expression of EARS2 (p < .002) and COG7 (p = .074) as well as lesser muscle concentrations of C2- and C3-acylcarnitines (p = .026). CONCLUSIONS:Our observations imply that exercise intervention dropout is genetically moderated through alterations in gene expression and metabolic pathways in skeletal muscle. Individual genetic traits may allow the development of a biomarker-based approach for identifying individuals who may benefit from more intensive counseling and other interventions to optimize exercise intervention adoption. CLINICAL TRIAL INFORMATION:STRRIDE I = NCT00200993; STRRIDE AT/RT = NCT00275145; STRRIDE-PD = NCT00962962.

OBJECTIVE:We aimed to characterise self-reported military and occupational exposures including Agent Orange, chemical/biological warfare agents, solvents, fuels, pesticides, metals and burn pits among Veterans in the Department of Veterans Affairs Million Veteran Program (MVP). METHODS:MVP is an ongoing longitudinal cohort and mega-biobank of over one million US Veterans. Over 500 000 MVP participants reported military exposures on the baseline survey, and over 300 000 reported occupational exposures on the lifestyle survey. We determined frequencies of selected self-reported occupational exposures by service era, specific deployment operation (1990-1991 Gulf War, Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF)), service in a combat zone and occupational categories. We also explored differences in self-reported exposures by sex and race. RESULTS:Agent Orange exposure was mainly reported by Vietnam-era Veterans. Gulf War and OEF/OIF Veterans deployed to a combat zone were more likely to report exposures to burn pits, chemical/biological weapons, anthrax vaccination and pyridostigmine bromide pill intake as compared with non-combat deployers and those not deployed. Occupational categories related to combat (infantry, combat engineer and helicopter pilot) often had the highest percentages of self-reported exposures, whereas those in healthcare-related occupations (dentists, physicians and occupational therapists) tended to report exposures much less often. Self-reported exposures also varied by race and sex. CONCLUSIONS:Our results demonstrate that the distribution of self-reported exposures varied by service era, demographics, deployment, combat experience and military occupation in MVP. Overall, the pattern of findings was consistent with previous population-based studies of US military Veterans.

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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.

Objectives: To examine whether severe Gulf War illness (SGWI) case status was associated with longitudinal multimorbidity patterns. Methods: Participants were users of the Veteran Health Administration Health Care System drawn from the Gulf War Era Cohort and Biorepository (n = 840). Longitudinal measures of multimorbidity were constructed using (1) electronic health records (Charlson Comorbidity Index; Elixhauser; and Veterans Affairs Frailty Index) from 10/1/1999 to 6/30/2023 and (2) self-reported medical conditions (Deficit Accumulation Index) since the war until the survey date. Accelerated failure time models examined SGWI case status as a predictor of time until threshold level of multimorbidity was reached, adjusted for age and sociodemographic and military characteristics. Results: Models, adjusted for covariates, revealed that (1) relative to the SWGI- group, the SGWI+ group was associated with an accelerated time for reaching each threshold and (2) the relationship between SGWI and each threshold was not moderated by age. Discussion: Findings suggest that veterans with SGWI experienced accelerated aging.

BackgroundVeterans of the first Gulf War (1990-1991) are reaching middle and older adulthood in differing degrees of health and biological age. Many Gulf War veterans report myriad negative symptoms classified as Gulf War illness (GWI), a chronic multi-symptom illness.ObjectivesTo describe and analyze deficit accumulation, among veterans with Severe GWI (SGWI+) and those without Severe GWI (SGWI-), to assess the association between a medically unexplained illness and aging.DesignThis study uses a retrospective cohort design with quasi-longitudinal data.SettingThe recruitment sample included 10,042 Gulf War era veterans across all four US Census regions.ParticipantsThe analytic sample included 1,054 participants of the GWECB for whom SGWI case status could be determined and who had valid responses for at least 90% of the deficits included in the deficit accumulation index.MeasurementsChronic health conditions were retroactively reported, including year of diagnosis, enabling us to create a longitudinal measure of deficit accumulation. This deficit accumulation index (DAI) ranged from 0-1 for each respondent in each year between 1991-2013. We compare veterans with SGWI+ to those with SGWI- using the CDC case definition.ResultsMost veterans in our sample could expect to spend more years with moderate or substantial deficits than without deficits. SGWI+ was associated with spending more years with substantial deficits than those with SGWI-. Veterans in middle age (age 35-65) experienced more years with substantial deficits than younger veterans. Individuals with SGWI+ had 13 times the hazard of accumulating substantial deficits than those without.ConclusionsThis study demonstrated that veterans with SGWI+, even those in midlife, experienced aging as measured by accumulating deficits. Practitioners should consider patients with multi-symptom illnesses as at risk of accelerated aging, tailoring treatments to address patients' holistic needs.

Supplementary Table S3 shows model fit statistics for five different sets if nested models calculated in this study: 1) Full Cohort; 2) Over 50 years old participants only; 3) Black race participants only; 4) Those who had at least one identified colonoscopy only; and 5) Those who had no history of other cancers only.