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People with lower levels of social connection are at increased risk for suicidal thoughts and behaviors. This extends to populations at greater risk of death by suicide, including U.S. military veterans. Despite this well-established association, it is unclear which measures of social connection are most useful in identifying veterans who could benefit from intervention to prevent suicide. To this end, we used data from the Million Veteran Program (MVP) to investigate the measures of social connection most strongly associated with suicidal thoughts and behaviors. Our sample included 264,626 veterans who reported on three measures of social connection-marital status, household size, and perceived social support-and were assessed for suicidal thoughts and behaviors using electronic health records. Veterans who were partnered (OR = 0.78, 95% CI [0.76-0.80], p < .001), living with others (OR = 0.71, 95% CI [0.70-0.73], p < .001), or reported higher levels of social support (OR = 0.67, 95% CI [0.65-0.69], p < .001), were less likely to have suicidal thoughts and behaviors. These associations varied by veterans' age, sex, and era of military service. When combined into a single risk score, lower levels of social connection were associated with greater likelihood of suicidal thoughts and behaviors (β = 1.42, 95% CI [1.40-1.43], p < .001). Social support, particularly positive social interactions, showed the strongest associations with suicidal thoughts and behaviors in elastic net regression models. Common measures of social connection, particularly social support, could be useful in assessing suicide risk and treatment needs for veterans., Competing Interests: Declaration of competing interest The authors have no outside interests to declare., (Published by Elsevier Ltd.)

Background: Risk for colorectal cancer may accumulate through multiple environmental factors. Understanding their effects, along with genetics, age, and family history, could allow improvements in clinical decisions for screening protocols. We aimed to extend the previous work by recalibrating an environmental risk score (e-Score) for colorectal cancer among a sample of US veteran participants of the Million Veteran Program., Methods: Demographic, lifestyle, and colorectal cancer data from 2011 to 2022 were abstracted from survey responses and health records of 227,504 male Million Veteran Program participants. Weighting for each environmental factor's effect size was recalculated using Veterans Affairs training data to create a recalibrated e-Score. This recalibrated score was compared with the original weighted e-Score in a validation sample of 113,752 (n cases = 590). Nested multiple logistic regression models tested associations between quintiles for recalibrated and original e-Scores. Likelihood ratio tests were used to compare model performance., Results: Age (P < 0.0001), education (P < 0.0001), diabetes (P < 0.0001), physical activity (P < 0.0001), smoking (P < 0.0001), NSAID use (P < 0.0001), calcium (P = 0.015), folate (P = 0.020), and fruit consumption (P = 0.019) were significantly different between colorectal cancer case and control groups. In the validation sample, the recalibrated e-Score model significantly improved the base model performance (P < 0.001), but the original e-Score model did not (P = 0.07). The recalibrated e-Score model quintile 5 was associated with significantly higher odds for colorectal cancer compared with quintile 1 (Q5 vs. Q1: 1.79; 95% CI, 1.38-2.33)., Conclusions: Multiple environmental factors and the recalibrated e-Score quintiles were significantly associated with colorectal cancer cases., Impact: A recalibrated, veteran-specific e-Score could be used to help personalize colorectal cancer screening and prevention strategies., (©2024 The Authors; Published by the American Association for Cancer Research.)

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).)

Objective: Low neuroticism, high extraversion, and high conscientiousness are related to physical activity (PA). We tested whether the small size and heterogeneity of these relationships result because personality traits influence one another as well as because some narrow facets rather than the broad domains contain more specific variance relevant to PA., Method: Participants were men and women enrolled in the University of North Carolina Alumni Heart Study who completed the Revised NEO Personality Inventory (NEO-PI-R) and reported their past month's average activity on an 8-point scale. In Study 1, we examined prospective correlations between the five NEO-PI-R domains and PA. In Studies 2 and 3, we used multinomial logistic regression to examine associations between PA and trait pair combinations (personality styles) controlling for age, sex, educational achievement, relationship status, and depression., Results: Study 1 revealed that lower neuroticism (N) and agreeableness (A) and higher conscientiousness (C) predicted more PA. Taken together, Studies 2 and 3 found that the combination of high Extraversion (E) and high openness (O) was related to higher PA and that combinations of low E and high A and low E and low C were related to lower PA. Study 3, which examined the activity facet of E (E4), found that E4 is an important driver of E-PA associations., Conclusions: Personality traits do not operate in isolation. They may influence how other traits are expressed and such nonadditive effects can impact PA. Assessment of personality styles could help to identify individuals at risk for PA avoidance and may be useful for developing personalized interventions. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

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., Competing Interests: Conflicts of Interest. The authors of this manuscript do not report any conflicts. The results of the present study do not constitute endorsement by ACSM. The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation.

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 × 10 -16 ), Hannum Age (1.81, 95% CI = 0.65, 2.98, P = 2.30 × 10 -3 ), and Phenotypic Age (2.88, 95% CI = 1.91, 3.87, P = 1.21 × 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: 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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Behavioral Medicine.)

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., 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.

Gulf War illness (GWI) is a chronic multisymptom disorder of unknown etiology that is believed to be caused by neurotoxicant exposure experienced during deployment to the Gulf War. Posttraumatic stress disorder (PTSD) covaries with GWI and is believed to play a role in GWI symptoms. The present study examined the association between self-reported military exposures and GWI, stratified by PTSD status, in veterans from the Gulf War Era Cohort and Biorepository who were deployed to the Persian Gulf during the war. Participants self-reported current GWI and PTSD symptoms as well as military exposures (e.g., pyridostigmine [PB] pills, pesticides/insecticides, combat, chemical attacks, and oil well fires) experienced during the Gulf War. Deployed veterans' (N = 921) GWI status was ascertained using the Centers for Disease Control and Prevention definition. Individuals who met the GWI criteria were stratified by PTSD status, yielding three groups: GWI-, GWI+/PTSD-, and GWI+/PTSD+. Multivariable logistic regression, adjusted for covariates, was used to examine associations between GWI/PTSD groups and military exposures. Apart from insect bait use, the GWI+/PTSD+ group had higher odds of reporting military exposures than the GWI+/PTSD- group, adjusted odds ratio (aOR) = 2.15, 95% CI [1.30, 3.56]-aOR = 6.91, 95% CI [3.39, 14.08]. Except for PB pills, the GWI+/PTSD- group had a higher likelihood of reporting military exposures than the GWI- group, aOR = 2.03, 95% CI [1.26, 3.26]-aOR = 4.01, 95% CI [1.57, 10.25]. These findings are consistent with roles for both PTSD and military exposures in the etiology of GWI., (© 2023 International Society for Traumatic Stress Studies.)

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.

Background: Veterans 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., Objectives: To 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., Design: This study uses a retrospective cohort design with quasi-longitudinal data., Setting: The recruitment sample included 10,042 Gulf War era veterans across all four US Census regions., Participants: The 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., Measurements: Chronic 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., Results: Most 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., Conclusions: This 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., Competing Interests: On behalf of all authors, the corresponding author states that there is no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

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 prespecified 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: Approximately 30% of the 700 000 Gulf War veterans report a chronic symptom-based illness of varying severity referred to as Gulf War illness (GWI). Toxic deployment-related exposures have been implicated in the cause of GWI, some of which contribute to metabolic dysregulation and lipid abnormalities. As this cohort ages, the relationship between GWI and atherosclerotic cardiovascular disease (ASCVD) is a growing concern. We evaluated associations between GWI and ASCVD, diabetes, hyperlipidemia, and hypertension in veterans of the Gulf War (1990-1991)., Methods and Results: Analysis of survey data collected in 2014 to 2016 from a national sample of deployed Gulf War veterans (n=942) and Veterans Health Administration electronic health record data (n=669). Multivariable logistic regression models tested for associations of GWI with self-reported ASCVD, diabetes, hyperlipidemia, and hypertension, controlling for confounding factors. Separate models tested for GWI associations with ASCVD and risk factors documented in the electronic health record. GWI was associated with self-reported hypertension (adjusted odds ratio [aOR], 1.67 [95% CI, 1.18-2.36]), hyperlipidemia (aOR, 1.46 [95% CI, 1.03-2.05]), and ASCVD (aOR, 2.65 [95% CI, 1.56-4.51]). In the subset of veterans with electronic health record data, GWI was associated with documented diabetes (aOR, 2.34 [95% CI, 1.43-3.82]) and hypertension (aOR, 2.84 [95% CI, 1.92-4.20]). Hyperlipidemia and hypertension served as partial mediators of the association between GWI and self-reported ASCVD., Conclusions: Gulf War veterans with GWI had higher odds of hyperlipidemia, hypertension, diabetes, and ASCVD compared with Gulf War veterans without GWI. Further examination of the mechanisms underlying this association, including a possible shared exposure-related mechanism, is necessary.

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).)

Previous studies have hypothesized that autozygosity is decreasing over generational time. However, these studies were limited to relatively small samples (n < 11,000) lacking in diversity, which may limit the generalizability of their findings. We present data that partially support this hypothesis from three large cohorts of diverse ancestries, two from the US (All of Us, n = 82,474; the Million Veteran Program, n = 622,497) and one from the UK (UK Biobank, n = 380,899). Our results from a mixed-effect meta-analysis demonstrate an overall trend of decreasing autozygosity over generational time (meta-analyzed slope = -0.029, SE = 0.009, p = 6.03e-4). On the basis of our estimates, we would predict F ROH to decline 0.29% for every 20-year increase in birth year. We determined that a model including an ancestry-by-country interaction term fit the data best, indicating that ancestry differences in this trend differ by country. We found further evidence to suggest a difference between the US and UK cohorts by meta-analyzing within country, observing a significant negative estimate in the US cohorts (meta-analyzed slope = -0.058, SE = 0.015, p = 1.50e-4) but a non-significant estimate in the UK (meta-analyzed slope = -0.001, SE = 0.008, p = 0.945). The association between autozygosity and birth year was substantially attenuated when accounting for educational attainment and income (meta-analyzed slope = -0.011, SE = 0.008, p = 0.167), suggesting they may partially account for decreasing autozygosity over time. Overall, we demonstrate decreasing autozygosity over time in a large, modern sample and speculate that this trend can be attributed to increases in urbanization and panmixia and differences in sociodemographic processes lead to country-specific differences in the rate of decline., Competing Interests: Declaration of interests R.P. is paid for their editorial work on the journal Complex Psychiatry and reports a research grant from Alkermes., (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Gulf War Illness (GWI) is a chronic, multi-symptom disorder affecting 25%-32% of Gulf War veterans. Veterans with GWI disproportionately suffer from gastrointestinal (GI) disorders. Given the increasing evidence supporting a gut-brain axis, we explore the relationship between post-traumatic stress disorder (PTSD), GWI, and self-reported GI disorders among GW veterans., Methods: Veterans from the Gulf War Era Cohort and Biorepository responded to a mail-based survey (N = 1058). They were stratified by GWI (Centers for Disease Control definition) and PTSD status. This yielded three groups: GWI-, GWI+/PTSD-, and GWI+/PTSD+. Multivariable logistic regression adjusting for demographic and military characteristics examined associations between GWI/PTSD groups and GI disorders. Results were expressed as adjusted odds ratios (aOR) with 95% confidence intervals (95% CI)., Key Results: The most frequently reported GI disorders were irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD), and colon polyps (CP). The GWI+/PTSD+ group had a higher odds of these disorders than the GWI+/PTSD- group (aOR IBS  = 3.12, 95% CI: 1.93-5.05; aOR GERD  = 2.04, 95% CI: 1.44-2.90; aOR CP  = 1.85, 95% CI: 1.23-2.80), which had a higher odds of these disorders than the GWI- group (aOR IBS  = 4.38, 95% CI: 1.55-12.36; aOR GERD  = 2.51 95% CI: 1.63-3.87; aOR CP  = 2.57, 95% CI: 1.53-4.32)., Conclusions & Inferences: GW veterans with GWI and PTSD have significantly higher odds of specific self-reported GI disorders than the other groups. Given the known bidirectional influences of the gut and brain, these veterans may benefit from a holistic healthcare approach that considers biopsychosocial contributors to the assessment and management of disease., (© 2023 John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Suicidal ideation (SI) often precedes and predicts suicide attempt and death, is the most common suicidal phenotype and is over-represented in veterans. The genetic architecture of SI in the absence of suicide attempt (SA) is unknown, yet believed to have distinct and overlapping risk with other suicidal behaviors. We performed the first GWAS of SI without SA in the Million Veteran Program (MVP), identifying 99,814 SI cases from electronic health records without a history of SA or suicide death (SD) and 512,567 controls without SI, SA or SD. GWAS was performed separately in the four largest ancestry groups, controlling for sex, age and genetic substructure. Ancestry-specific results were combined via meta-analysis to identify pan-ancestry loci. Four genome-wide significant (GWS) loci were identified in the pan-ancestry meta-analysis with loci on chromosomes 6 and 9 associated with suicide attempt in an independent sample. Pan-ancestry gene-based analysis identified GWS associations with DRD2, DCC, FBXL19, BCL7C, CTF1, ANNK1, and EXD3. Gene-set analysis implicated synaptic and startle response pathways (q's<0.05). European ancestry (EA) analysis identified GWS loci on chromosomes 6 and 9, as well as GWS gene associations in EXD3, DRD2, and DCC. No other ancestry-specific GWS results were identified, underscoring the need to increase representation of diverse individuals. The genetic correlation of SI and SA within MVP was high (rG = 0.87; p = 1.09e-50), as well as with post-traumatic stress disorder (PTSD; rG = 0.78; p = 1.98e-95) and major depressive disorder (MDD; rG = 0.78; p = 8.33e-83). Conditional analysis on PTSD and MDD attenuated most pan-ancestry and EA GWS signals for SI without SA to nominal significance, with the exception of EXD3 which remained GWS. Our novel findings support a polygenic and complex architecture for SI without SA which is largely shared with SA and overlaps with psychiatric conditions frequently comorbid with suicidal behaviors., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Oxytocin (OT), the brain's most abundant neuropeptide, plays an important role in social salience and motivation. Clinical trials of the efficacy of OT in autism spectrum disorder (ASD) have reported mixed results due in part to ASD's complex etiology. We investigated whether genetic and epigenetic variation contribute to variable endogenous OT levels that modulate sensitivity to OT therapy. To carry out this analysis, we integrated genome-wide profiles of DNA-methylation, transcriptional activity, and genetic variation with plasma OT levels in 290 participants with ASD enrolled in a randomized controlled trial of OT. Our analysis identified genetic variants with novel association with plasma OT, several of which reside in known ASD risk genes. We also show subtle but statistically significant association of plasma OT levels with peripheral transcriptional activity and DNA-methylation profiles across several annotated gene sets. These findings broaden our understanding of the effects of the peripheral oxytocin system and provide novel genetic candidates for future studies to decode the complex etiology of ASD and its interaction with OT signaling and OT-based interventions. LAY SUMMARY: Oxytocin (OT) is an abundant chemical produced by neurons that plays an important role in social interaction and motivation. We investigated whether genetic and epigenetic factors contribute to variable OT levels in the blood. To this, we integrated genetic, gene expression, and non-DNA regulated (epigenetic) signatures with blood OT levels in 290 participants with autism enrolled in an OT clinical trial. We identified genetic association with plasma OT, several of which reside in known autism risk genes. We also show statistically significant association of plasma OT levels with gene expression and epigenetic across several gene pathways. These findings broaden our understanding of the factors that influence OT levels in the blood for future studies to decode the complex presentation of autism and its interaction with OT and OT-based treatment., (© 2023 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.)

Importance: Suicide is a leading cause of death; however, the molecular genetic basis of suicidal thoughts and behaviors (SITB) remains unknown., Objective: To identify novel, replicable genomic risk loci for SITB., Design, Setting, and Participants: This genome-wide association study included 633 778 US military veterans with and without SITB, as identified through electronic health records. GWAS was performed separately by ancestry, controlling for sex, age, and genetic substructure. Cross-ancestry risk loci were identified through meta-analysis. Study enrollment began in 2011 and is ongoing. Data were analyzed from November 2021 to August 2022., Main Outcome and Measures: SITB., Results: A total of 633 778 US military veterans were included in the analysis (57 152 [9%] female; 121 118 [19.1%] African ancestry, 8285 [1.3%] Asian ancestry, 452 767 [71.4%] European ancestry, and 51 608 [8.1%] Hispanic ancestry), including 121 211 individuals with SITB (19.1%). Meta-analysis identified more than 200 GWS (P < 5 × 10-8) cross-ancestry risk single-nucleotide variants for SITB concentrated in 7 regions on chromosomes 2, 6, 9, 11, 14, 16, and 18. Top single-nucleotide variants were largely intronic in nature; 5 were independently replicated in ISGC, including rs6557168 in ESR1, rs12808482 in DRD2, rs77641763 in EXD3, rs10671545 in DCC, and rs36006172 in TRAF3. Associations for FBXL19 and AC018880.2 were not replicated. Gene-based analyses implicated 24 additional GWS cross-ancestry risk genes, including FURIN, TSNARE1, and the NCAM1-TTC12-ANKK1-DRD2 gene cluster. Cross-ancestry enrichment analyses revealed significant enrichment for expression in brain and pituitary tissue, synapse and ubiquitination processes, amphetamine addiction, parathyroid hormone synthesis, axon guidance, and dopaminergic pathways. Seven other unique European ancestry-specific GWS loci were identified, 2 of which (POM121L2 and METTL15/LINC02758) were replicated. Two additional GWS ancestry-specific loci were identified within the African ancestry (PET112/GATB) and Hispanic ancestry (intergenic locus on chromosome 4) subsets, both of which were replicated. No GWS loci were identified within the Asian ancestry subset; however, significant enrichment was observed for axon guidance, cyclic adenosine monophosphate signaling, focal adhesion, glutamatergic synapse, and oxytocin signaling pathways across all ancestries. Within the European ancestry subset, genetic correlations (r > 0.75) were observed between the SITB phenotype and a suicide attempt-only phenotype, depression, and posttraumatic stress disorder. Additionally, polygenic risk score analyses revealed that the Million Veteran Program polygenic risk score had nominally significant main effects in 2 independent samples of veterans of European and African ancestry., Conclusions and Relevance: The findings of this analysis may advance understanding of the molecular genetic basis of SITB and provide evidence for ESR1, DRD2, TRAF3, and DCC as cross-ancestry candidate risk genes. More work is needed to replicate these findings and to determine if and how these genes might impact clinical care.

Objective: This study aimed to determine whether novel biomarkers of cardiometabolic health improve in response to a 12-month behavioral weight-loss intervention and to compare benefits of diet alone with diet plus physical activity for these biomarkers., Methods: Participants (N = 374) were randomized to either diet alone (DIET), diet plus 150 min/wk of prescribed moderate-intensity physical activity (DIET + PA150), or diet plus 250 min/wk of prescribed moderate-intensity physical activity (DIET + PA250). Biomarker concentrations were determined using nuclear magnetic resonance spectroscopy. Mixed models assessed for a time effect, group effect, or group by time interaction., Results: All groups significantly improved body weight (time: p < 0.0001), Lipoprotein Insulin Resistance Index score (time: p < 0.0001), Diabetes Risk Index score (time: p < 0.0001), branched-chain amino acid concentration (time: p < 0.0001), and GlycA concentration (time: p < 0.0001), with no group effect or group by time interactions., Conclusions: All intervention groups prompted a notable beneficial change among biomarkers of insulin resistance and cardiometabolic health. However, the addition of at least moderate-intensity physical activity to a diet-only intervention did not provide any additional benefit. These findings highlight that an average weight loss of approximately 10% profoundly impacts biomarkers of insulin resistance and cardiometabolic disease in adults with overweight or obesity., (© 2023 The Obesity Society.)

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.

Genetically tractable animal models provide needed strategies to resolve the biological basis of drug addiction. Intravenous self-administration (IVSA) is the gold standard for modeling psychostimulant and opioid addiction in animals, but technical limitations have precluded the widespread use of IVSA in mice. Here, we describe IVSA paradigms for mice that capture the multi-stage nature of the disorder and permit predictive modeling. In these paradigms, C57BL/6J mice with long-standing indwelling jugular catheters engaged in cocaine- or remifentanil-associated lever responding that was fixed ratio-dependent, dose-dependent, extinguished by withholding the drug, and reinstated by the presentation of drug-paired cues. The application of multivariate analysis suggested that drug taking in both paradigms was a function of two latent variables we termed incentive motivation and discriminative control. Machine learning revealed that vulnerability to drug seeking and relapse were predicted by a mouse's a priori response to novelty, sensitivity to drug-induced locomotion, and drug-taking behavior. The application of these behavioral and statistical-analysis approaches to genetically-engineered mice will facilitate the identification of neural circuits driving addiction susceptibility and relapse and focused therapeutic development., (© 2022. The Author(s).)

Background: Epigenetic age is a DNA methylation-based biomarker of aging that is accurate across the lifespan and a range of cell types. The difference between epigenetic age and chronological age, termed age acceleration (AA), is a strong predictor of lifespan and healthspan. The predictive capabilities of AA for all-cause mortality have been evaluated in the general population; however, its utility is less well evaluated in those with chronic conditions. Additionally, the pathophysiologic pathways whereby AA predicts mortality are unclear. We hypothesized that AA predicts mortality in individuals with underlying cardiovascular disease; and the association between AA and mortality is mediated, in part, by vascular and cardiometabolic measures., Methods: We evaluated 562 participants in an urban, three-county area of central North Carolina from the CATHGEN cohort, all of whom received a cardiac catheterization procedure. We analyzed three AA biomarkers, Horvath epigenetic age acceleration (HAA), phenotypic age acceleration (PhenoAA), and Grim age acceleration (GrimAA), by Cox regression models, to assess whether AAs were associated with all-cause mortality. We also evaluated if these associations were mediated by vascular and cardiometabolic outcomes, including left ventricular ejection fraction (LVEF), blood cholesterol concentrations, angiopoietin-2 (ANG2) protein concentration, peripheral artery disease, coronary artery disease, diabetes, and hypertension. The total effect, direct effect, indirect effect, and percentage mediated were estimated using pathway mediation tests with a regression adjustment approach., Results: PhenoAA (HR = 1.05, P < 0.0001), GrimAA (HR = 1.10, P < 0.0001) and HAA (HR = 1.03, P = 0.01) were all associated with all-cause mortality. The association of mortality and PhenoAA was partially mediated by ANG2, a marker of vascular function (19.8%, P = 0.016), and by diabetes (8.2%, P = 0.043). The GrimAA-mortality association was mediated by ANG2 (12.3%, P = 0.014), and showed weaker evidence for mediation by LVEF (5.3%, P = 0.065)., Conclusions: Epigenetic age acceleration remains strongly predictive of mortality even in individuals already burdened with cardiovascular disease. Mortality associations were mediated by ANG2, which regulates endothelial permeability and angiogenic functions, suggesting that specific vascular pathophysiology may link accelerated epigenetic aging with increased mortality risks., (© 2022. The Author(s).)

Purpose: This study aimed to characterize the timing and self-reported determinants of exercise dropout among sedentary adults with overweight or obesity. We also sought to explore variations in adherence among individuals who completed a 6- to 8-month structured exercise intervention., Methods: A total of 947 adults with dyslipidemia [STRRIDE I, STRRIDE AT/RT] or prediabetes [STRRIDE-PD] were enrolled to either control or to one of 10 exercise interventions, ranging from doses of 8-23 kcal/kg/week; intensities of 50%-75% V̇O2 peak; and durations of 6-8 months. Two groups included resistance training and one included dietary intervention (7% weight loss goal). Dropout was defined as an individual who withdrew from the study due a variety of determinants. Timing of intervention dropout was defined as the last session attended and categorized into phases. Exercise training adherence was calculated by dividing weekly minutes or total sets of exercise completed by weekly minutes or total sets of exercise prescribed. General linear models were used to characterize the associations between timing of dropout and determinant category., Results: Compared to exercise intervention completers (n=652), participants who dropped out (n=295) were on average non-white (98% vs. 80%, p<0.01), had higher body mass index (31.0 kg/m 2 vs. 30.2 kg/m 2 ; p<0.01), and were less fit at baseline (25.0 mg/kg/min vs. 26.7 ml/kg/min, p<0.01). Of those who dropped out, 67% did so prior to the start of or while ramping up to the prescribed exercise volume and intensity. The most commonly reported reason for dropout was lack of time (40%). Notably, among individuals who completed the ramp training period, subsequent exercise intervention adherence did not waiver over the ensuing 6-8 months of training., Conclusion: These findings are some of the first to delineate associations between the timing of dropout and dropout determinants, providing guidance to future exercise interventions to better support individuals at-risk for dropout.

Exposure to air pollution is a major risk factor for cardiovascular disease, disease risk factors, and mortality. Specifically, particulate matter (PM), and to some extent ozone, are contributors to these effects. In addition, exposures to these pollutants may be especially dangerous for susceptible populations. In this repeated-visit panel study, cardiovascular markers were collected from thirteen male participants with stable coronary artery disease. For 0-4 days prior to the health measurement collections, daily concentrations of fine PM (PM 2.5 ) and ozone were obtained from local central monitoring stations located near the participant's homes. Then, single (PM 2.5 ) and two-pollutant (PM 2.5 and ozone) models were used to assess whether there were short-term changes in cardiovascular health markers. Per interquartile range increase in PM 2.5 , there were decrements in several heart rate variability metrics, including the standard deviation of the normal-to-normal intervals (lag 3, -5.8%, 95% confidence interval (CI) = -11.5, 0.3) and root-mean squared of successive differences (five day moving average, -8.1%, 95% CI = -15.0, -0.7). In addition, increases in PM 2.5 were also associated with changes in P complexity (lag 1, 4.4%, 95% CI = 0.5, 8.5), QRS complexity (lag 1, 4.9%, 95% CI = 1.4, 8.5), total cholesterol (five day moving average, -2.1%, 95% CI = -4.1, -0.1), and high-density lipoprotein cholesterol (lag 2, -1.6%, 95% CI = -3.1, -0.1). Comparisons to our previously published work on ozone were conducted. We found that ozone affected inflammation and endothelial function, whereas PM 2.5 influenced heart rate variability, repolarization, and lipids. All the health changes from these two studies were found at concentrations below the United States Environmental Protection Agency's National Ambient Air Quality Standards. Our results imply clear differences in the cardiovascular outcomes observed with exposure to the two ubiquitous air pollutants PM 2.5 and ozone; this observation suggests different mechanisms of toxicity for these exposures., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background and Aims: Data are limited regarding colonoscopy risk during long-term, programmatic colorectal cancer screening and follow-up. We aimed to describe adverse events during follow-up in a colonoscopy screening program after the baseline examination and examine factors associated with increased risk., Methods: Cooperative Studies Program no. 380 includes 3121 asymptomatic veterans aged 50 to 75 years who underwent screening colonoscopy between 1994 and 1997. Periprocedure adverse events requiring significant intervention were defined as major events (other events were minor) and were tracked during follow-up for at least 10 years. Multivariable odds ratios (ORs) were calculated for factors associated with risk of follow-up adverse events., Results: Of 3727 follow-up examinations in 1983 participants, adverse events occurred in 105 examinations (2.8%) in 93 individuals, including 22 major and 87 minor events (examinations may have had >1 event). Incidence of major events (per 1000 examinations) remained relatively stable over time, with 6.1 events at examination 2, 4.8 at examination 3, and 7.2 at examination 4. Examinations with major events included 1 perforation, 3 GI bleeds requiring intervention, and 17 cardiopulmonary events. History of prior colonoscopic adverse events was associated with increased risk of events (major or minor) during follow-up (OR, 2.7; 95% confidence interval, 1.6-4.6)., Conclusions: Long-term programmatic screening and surveillance was safe, as major events were rare during follow-up. However, serious cardiopulmonary events were the most common major events. These results highlight the need for detailed assessments of comorbid conditions during routine clinical practice, which could help inform individual decisions regarding the utility of ongoing colonoscopy follow-up., (Published by Elsevier Inc.)

We report a genome-wide association study (GWAS) of coronary artery disease (CAD) incorporating nearly a quarter of a million cases, in which existing studies are integrated with data from cohorts of white, Black and Hispanic individuals from the Million Veteran Program. We document near equivalent heritability of CAD across multiple ancestral groups, identify 95 novel loci, including nine on the X chromosome, detect eight loci of genome-wide significance in Black and Hispanic individuals, and demonstrate that two common haplotypes at the 9p21 locus are responsible for risk stratification in all populations except those of African origin, in which these haplotypes are virtually absent. Moreover, in the largest GWAS for angiographically derived coronary atherosclerosis performed to date, we find 15 loci of genome-wide significance that robustly overlap with established loci for clinical CAD. Phenome-wide association analyses of novel loci and polygenic risk scores (PRSs) augment signals related to insulin resistance, extend pleiotropic associations of these loci to include smoking and family history, and precisely document the markedly reduced transferability of existing PRSs to Black individuals. Downstream integrative analyses reinforce the critical roles of vascular endothelial, fibroblast, and smooth muscle cells in CAD susceptibility, but also point to a shared biology between atherosclerosis and oncogenesis. This study highlights the value of diverse populations in further characterizing the genetic architecture of CAD., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Height has been associated with many clinical traits but whether such associations are causal versus secondary to confounding remains unclear in many cases. To systematically examine this question, we performed a Mendelian Randomization-Phenome-wide association study (MR-PheWAS) using clinical and genetic data from a national healthcare system biobank., Methods and Findings: Analyses were performed using data from the US Veterans Affairs (VA) Million Veteran Program in non-Hispanic White (EA, n = 222,300) and non-Hispanic Black (AA, n = 58,151) adults in the US. We estimated height genetic risk based on 3290 height-associated variants from a recent European-ancestry genome-wide meta-analysis. We compared associations of measured and genetically-predicted height with phenome-wide traits derived from the VA electronic health record, adjusting for age, sex, and genetic principal components. We found 345 clinical traits associated with measured height in EA and an additional 17 in AA. Of these, 127 were associated with genetically-predicted height at phenome-wide significance in EA and 2 in AA. These associations were largely independent from body mass index. We confirmed several previously described MR associations between height and cardiovascular disease traits such as hypertension, hyperlipidemia, coronary heart disease (CHD), and atrial fibrillation, and further uncovered MR associations with venous circulatory disorders and peripheral neuropathy in the presence and absence of diabetes. As a number of traits associated with genetically-predicted height frequently co-occur with CHD, we evaluated effect modification by CHD status of genetically-predicted height associations with risk factors for and complications of CHD. We found modification of effects of MR associations by CHD status for atrial fibrillation/flutter but not for hypertension, hyperlipidemia, or venous circulatory disorders., Conclusions: We conclude that height may be an unrecognized but biologically plausible risk factor for several common conditions in adults. However, more studies are needed to reliably exclude horizontal pleiotropy as a driving force behind at least some of the MR associations observed in this study., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: CJO is a full-time employee of Novartis Institutes of Biomedical Research. The remaining authors have declared that no competing interests exist.

Background: Colorectal cancer (CRC) screening guidelines recommend frequent colonoscopies and consideration of genetic testing in individuals with ≥10 cumulative adenomas. However, it is unclear how these guidelines apply to routine practice., Aims: We estimated the proportion of participants found to have ≥10 cumulative adenomas in a screening population and described their outcomes of advanced neoplasia (AN), CRC, and extra-colonic malignancy., Methods: We performed a secondary analysis of VA CSP#380, which includes 3121 veterans aged 50-75 who were followed up to 10 years after screening colonoscopy. We calculated the cumulative risk of ≥10 cumulative adenomas by Kaplan-Meier method. We compared baseline risk factors in those with and without ≥10 cumulative adenomas as well as the risk for AN (adenoma ≥1 cm, villous adenoma or high-grade dysplasia, or CRC) and extra-colonic malignancy by multivariate logistic regression., Results: The cumulative risk of ≥10 cumulative adenomas over 10.5 years was 6.51% (95% CI 4.38%-9.62%). Age 60-69 or 70-75 at baseline colonoscopy was the only factors associated with the finding of ≥10 cumulative adenomas. Compared to those with 0-9 cumulative adenomas, participants with ≥10 cumulative adenomas were more likely to have had AN (OR 17.03; 95% CI 9.41-30.84), including CRC (OR 7.00; 95% CI 2.84-17.28), but not extra-colonic malignancies., Conclusions: Approximately 6.5% of participants in this screening population were found to have ≥10 cumulative adenomas over 10.5 years, which was uncommon before age 60. These participants were found to have AN and CRC significantly more often compared to those with lower cumulative adenomas., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Rheumatoid arthritis (RA) T cells drive autoimmune features via metabolic reprogramming that reduces oxidative metabolism. Exercise training improves cardiorespiratory fitness (i.e., systemic oxidative metabolism) and thus may impact RA T cell oxidative metabolic function. In this pilot study of RA participants, we took advantage of heterogeneous responses to a high-intensity interval training (HIIT) exercise program to identify relationships between improvements in cardiorespiratory fitness with changes in peripheral T cell and skeletal muscle oxidative metabolism. In 12 previously sedentary persons with seropositive RA, maximal cardiopulmonary exercise tests, fasting blood, and vastus lateralis biopsies were obtained before and after 10 weeks of HIIT. Following HIIT, improvements in RA cardiorespiratory fitness were associated with changes in RA CD4 + T cell basal and maximal respiration and skeletal muscle carnitine acetyltransferase (CrAT) enzyme activity. Further, changes in CD4 + T cell respiration were associated with changes in naïve CD4 + CCR7 + CD45RA + T cells, muscle CrAT, and muscle medium-chain acylcarnitines and fat oxidation gene expression profiles. In summary, modulation of cardiorespiratory fitness and molecular markers of skeletal muscle oxidative metabolism during exercise training paralleled changes in T cell metabolism. Exercise training that improves RA cardiorespiratory fitness may therefore be valuable in managing pathologically related immune and muscle dysfunction.Trial registration: ClinicalTrials.gov, NCT02528344. Registered on 19 August 2015., (© 2022. The Author(s).)

Background: Ischemic coronary heart disease (IHD) is the leading cause of death worldwide. Genetic variation is presumed to be a major factor underlying sex differences for IHD events, including mortality. The purpose of this study was to identify sex-specific candidate genes associated with all-cause mortality among people diagnosed with coronary artery disease (CAD)., Methods: We performed a sex-stratified, exploratory genome-wide association (GWAS) screen using existing data from CAD-diagnosed males ( n = 510) and females ( n = 174) who reported European ancestry from the Duke Catheterization Genetics biorepository. Extant genotype data for 785,945 autosomal SNPs generated with the Human Omni1-Quad BeadChip (Illumina, CA, USA) were analyzed using an additive inheritance model. We estimated instantaneous risk of all-cause mortality by genotype groups across the 11-year follow-up using Cox multivariate regression, covarying for age and genomic ancestry., Results: The top GWAS hits associated with all-cause mortality among people with CAD included 8 SNPs among males and 15 among females ( p = 1 × 10 -6 or 10 -7 ), adjusted for covariates. Cross-sex comparisons revealed distinct candidate genes. Biologically relevant candidates included rs9932462 ( EMP2/TEKT5) and rs2835913 ( KCNJ6) among males and rs7217169 ( RAP1GAP2 ), rs8021816 ( PRKD1 ), rs8133010 ( PDE9A ), and rs12145981 ( LPGAT1 ) among females., Conclusions: We report 20 sex-specific candidate genes having suggestive association with all-cause mortality among CAD-diagnosed subjects. Findings demonstrate proof of principle for identifying sex-associated genetic factors that may help explain differential mortality risk in people with CAD. Replication and meta-analyses in larger studies with more diverse samples will strengthen future work in this area., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

This study examines how health-related quality of life (HRQOL) and related indices vary by Gulf War illness (GWI) case status. The study population included veterans from the Gulf War Era Cohort and Biorepository (n = 1116). Outcomes were physical and mental health from the Veterans RAND 12 and depression, post-traumatic stress (PTSD), sleep disturbance, and pain. Kansas (KS) and Centers for Disease Control and Prevention (CDC) GWI definitions were used. Kansas GWI derived subtypes included GWI (met symptom criteria; no exclusionary conditions (KS GWI: Sym+/Dx−)) and those without GWI: KS noncase (1): Sym+/Dx+, KS noncase (2): Sym−/Dx+, and noncase (3): Sym−/Dx−. CDC-derived subtypes included CDC GWI severe, CDC GWI mild-to-moderate and CDC noncases. Case status and outcomes were examined using multivariable regression adjusted for sociodemographic and military-related characteristics. Logistic regression analysis was used to examine associations between GWI case status and binary measures for depression, PTSD, and severe pain. The KS GWI: Sym+/Dx− and KS noncase (1): Sym+/Dx+ groups had worse mental and physical HRQOL outcomes than veterans in the KS noncase (2): Sym−/Dx+ and KS noncase (3): Sym−/Dx− groups (ps < 0.001). Individuals who met the CDC GWI severe criteria had worse mental and physical HRQOL outcomes than those meeting the CDC GWI mild-to-moderate or CDC noncases (ps < 0.001). For other outcomes, results followed a similar pattern. Relative to the less symptomatic comparison subtypes, veterans who met the Kansas symptom criteria, regardless of exclusionary conditions, and those who met the CDC GWI severe criteria experienced lower HRQOL and higher rates of depression, PTSD, and severe pain.

To identify pan-ancestry and ancestry-specific loci associated with attempting suicide among veterans, we conducted a genome-wide association study (GWAS) of suicide attempts within a large, multi-ancestry cohort of U.S. veterans enrolled in the Million Veterans Program (MVP). Cases were defined as veterans with a documented history of suicide attempts in the electronic health record (EHR; N = 14,089) and controls were defined as veterans with no documented history of suicidal thoughts or behaviors in the EHR (N = 395,064). GWAS was performed separately in each ancestry group, controlling for sex, age and genetic substructure. Pan-ancestry risk loci were identified through meta-analysis and included two genome-wide significant loci on chromosomes 20 (p = 3.64 × 10 -9 ) and 1 (p = 3.69 × 10 -8 ). A strong pan-ancestry signal at the Dopamine Receptor D2 locus (p = 1.77 × 10 -7 ) was also identified and subsequently replicated in a large, independent international civilian cohort (p = 7.97 × 10 -4 ). Additionally, ancestry-specific genome-wide significant loci were also detected in African-Americans, European-Americans, Asian-Americans, and Hispanic-Americans. Pathway analyses suggested over-representation of many biological pathways with high clinical significance, including oxytocin signaling, glutamatergic synapse, cortisol synthesis and secretion, dopaminergic synapse, and circadian rhythm. These findings confirm that the genetic architecture underlying suicide attempt risk is complex and includes both pan-ancestry and ancestry-specific risk loci. Moreover, pathway analyses suggested many commonly impacted biological pathways that could inform development of improved therapeutics for suicide prevention., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Introduction: Controversy exists regarding the impact of various risk factors on noncolorectal cancer (CRC) mortality in healthy screening populations. We examined the impact of known CRC risk factors, including baseline colonoscopy findings, on non-CRC mortality in a screening population., Methods: Cooperative Studies Program (CSP) #380 is comprised of 3,121 veterans aged 50-75 years who underwent screening colonoscopy from 1994 to 97 and were then followed for at least 10 years or until death. Hazard ratios (HRs) for risk factors on non-CRC mortality were estimated by multivariate Cox proportional hazards., Results: Current smoking (HR 2.12, 95% confidence interval [CI] 1.78-2.52, compared with nonsmokers) and physical activity (HR 0.89, 95% CI 0.84-0.93) were the modifiable factors most associated with non-CRC mortality in CSP#380. In addition, compared with no neoplasia at baseline colonoscopy, non-CRC mortality was higher in participants with ≥3 small adenomas (HR 1.43, 95% CI 1.06-1.94), advanced adenomas (HR 1.32, 95% CI 0.99-1.75), and CRC (HR 2.95, 95% CI 0.98-8.85). Those with 1-2 small adenomas were not at increased risk for non-CRC mortality (HR 1.15, 95% CI 0.94-1.4)., Discussion: In a CRC screening population, known modifiable risk factors were significantly associated with 10-year non-CRC mortality. Furthermore, those who died from non-CRC causes within 10 years were more likely to have had high-risk findings at baseline colonoscopy. These results suggest that advanced colonoscopy findings may be a risk marker of poor health outcomes. Integrated efforts are needed to motivate healthy lifestyle changes during CRC screening, particularly in those with high-risk colonoscopy findings and unaddressed risk factors., (Copyright © 2022 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Veterans with difficult-to-diagnose conditions who receive care in the Department of Veterans Affairs (VA) healthcare system can be referred for evaluation at one of three specialty VA War-Related Illness and Injury Study Centers (WRIISC). Veterans of the 1990−1991 Gulf War have long experienced excess rates of chronic symptoms associated with the condition known as Gulf War Illness (GWI), with hundreds evaluated at the WRIISC. Here we provide the first report from a cohort of 608 Gulf War Veterans seen at the WRIISC who completed questionnaires on chronic symptoms (>6 months) consistent with GWI as well as prominent exposures during Gulf War deployment. These included veterans’ reports of hearing chemical alarms/donning Military-Ordered Protective Posture Level 4 (MOPP4) gear, pesticide use, and use of pyridostigmine bromide (PB) pills as prophylaxis against the effects of nerve agents. Overall, veterans in the cohort were highly symptomatic and reported a high degree of exposures. In multivariable models, these exposures were significantly associated with moderate-to-severe chronic symptoms in neurocognitive/mood, fatigue/sleep, and pain domains. Specifically, exposure to pesticides was associated with problems with concentration and memory, problems sleeping, unrefreshing sleep, and joint pain. Use of MOPP4 was associated with light sensitivity and unrefreshing sleep and use of PB was associated with depression. We also evaluated the association of exposures with symptom summary scores based on veterans’ severity of symptoms in four domains and overall. In multivariable modeling, the pain symptom severity score was significantly associated with pesticide use (Odds ratio (OR): 4.13, 95% confidence intervals (CI): 1.78−9.57) and taking PB pills (OR: 2.28, 95% CI: 1.02−5.09), and overall symptom severity was significantly associated with use of PB pills (OR: 2.41, 95% CI: 1.01−5.75). Conclusion: Decades after deployment, Gulf War veterans referred to a VA tertiary evaluation center report a high burden of chronic symptoms, many of which were associated with reported neurotoxicant exposures during the war.

Aims: The F-actin-binding protein Drebrin inhibits smooth muscle cell (SMC) migration, proliferation, and pro-inflammatory signalling. Therefore, we tested the hypothesis that Drebrin constrains atherosclerosis., Methods and Results: SM22-Cre+/Dbnflox/flox/Ldlr-/- (SMC-Dbn-/-/Ldlr-/-) and control mice (SM22-Cre+/Ldlr-/-, Dbnflox/flox/Ldlr-/-, and Ldlr-/-) were fed a western diet for 14-20 weeks. Brachiocephalic arteries of SMC-Dbn -/-/Ldlr-/- mice exhibited 1.5- or 1.8-fold greater cross-sectional lesion area than control mice at 14 or 20 weeks, respectively. Aortic atherosclerotic lesion surface area was 1.2-fold greater in SMC-Dbn-/-/Ldlr-/- mice. SMC-Dbn-/-/Ldlr-/- lesions comprised necrotic cores that were two-fold greater in size than those of control mice. Consistent with their bigger necrotic core size, lesions in SMC-Dbn-/- arteries also showed more transdifferentiation of SMCs to macrophage-like cells: 1.5- to 2.5-fold greater, assessed with BODIPY or with CD68, respectively. In vitro data were concordant: Dbn-/- SMCs had 1.7-fold higher levels of KLF4 and transdifferentiated to macrophage-like cells more readily than Dbnflox/flox SMCs upon cholesterol loading, as evidenced by greater up-regulation of CD68 and galectin-3. Adenovirally mediated Drebrin rescue produced equivalent levels of macrophage-like transdifferentiation in Dbn-/- and Dbnflox/flox SMCs. During early atherogenesis, SMC-Dbn-/-/Ldlr-/- aortas demonstrated 1.6-fold higher levels of reactive oxygen species than control mouse aortas. The 1.8-fold higher levels of Nox1 in Dbn-/- SMCs were reduced to WT levels with KLF4 silencing. Inhibition of Nox1 chemically or with siRNA produced equivalent levels of macrophage-like transdifferentiation in Dbn-/- and Dbnflox/flox SMCs., Conclusion: We conclude that SMC Drebrin limits atherosclerosis by constraining SMC Nox1 activity and SMC transdifferentiation to macrophage-like cells., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders., Methods: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors., Results: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged., Conclusions: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders., (Copyright © 2021 Society of Biological Psychiatry. All rights reserved.)

Background: Neighborhood-level socioeconomic status (SES) is associated with health outcomes, including cardiovascular disease and diabetes, but these associations are rarely studied across large, diverse populations., Methods: We used Ward's Hierarchical clustering to define eight neighborhood clusters across North Carolina using 11 census-based indicators of SES, race, housing, and urbanicity and assigned 6992 cardiac catheterization patients at Duke University Hospital from 2001 to 2010 to clusters. We examined associations between clusters and coronary artery disease index > 23 (CAD), history of myocardial infarction, hypertension, and diabetes using logistic regression adjusted for age, race, sex, body mass index, region of North Carolina, distance to Duke University Hospital, and smoking status., Results: Four clusters were urban, three rural, and one suburban higher-middle-SES (referent). We observed greater odds of myocardial infarction in all six clusters with lower or middle-SES. Odds of CAD were elevated in the rural cluster that was low-SES and plurality Black (OR 1.16, 95% CI 0.94-1.43) and in the rural cluster that was majority American Indian (OR 1.31, 95% CI 0.91-1.90). Odds of diabetes and hypertension were elevated in two urban and one rural low- and lower-middle SES clusters with large Black populations., Conclusions: We observed higher prevalence of cardiovascular disease and diabetes in neighborhoods that were predominantly rural, low-SES, and non-White, highlighting the importance of public health and healthcare system outreach into these communities to promote cardiometabolic health and prevent and manage hypertension, diabetes and coronary artery disease., Competing Interests: Disclosure None., (Published by Elsevier Inc.)

About 25-35% of United States veterans who fought in the 1990-1991 Gulf War report several moderate or severe chronic systemic symptoms, defined as Gulf War illness (GWI). Thirty years later, there is little consensus on the causes or biological underpinnings of GWI. The Gulf War Era Cohort and Biorepository (GWECB) was designed to investigate genetic and environmental associations with GWI and consists of 1343 veterans. We investigate candidate gene-toxicant interactions that may be associated with GWI based on prior associations found in human and animal model studies, focusing on SNPs in or near ACHE , BCHE , and PON1 genes to replicate results from prior studies. SOD1 was also considered as a candidate gene. CDC Severe GWI, the primary outcome, was observed in 26% of the 810 deployed veterans included in this study. The interaction between the candidate SNP rs662 and pyridostigmine bromide (PB) pills was found to be associated with CDC Severe GWI. Interactions between PB pill exposure and rs3917545, rs3917550, and rs2299255, all in high linkage disequilibrium in PON1 , were also associated with respiratory symptoms. These SNPs could point toward biological pathways through which GWI may develop, which could lead to biomarkers to detect GWI or to better treatment options for veterans with GWI.

Aims: Gulf War illness (GWI), a chronic symptom-based disorder, affects up to 30% of Veterans who served in the 1990-1991 Gulf War 1 . Because no diagnostic test or code for GWI exists, researchers typically determine case status using self-reported symptoms and conditions according to Kansas 2 and CDC 3 criteria. No validated algorithm has been published and case definitions have varied slightly by study. This paper aims to standardize the application of the original CDC and Kansas case definitions by defining a framework for writing reliable code for complex case definitions, implementing this framework on a sample of 1343 Gulf War Veterans (GWVs), and validating the framework by applying the code to a sample of 41,077 GWVs., Main Methods: Methods were drawn from software engineering: write pseudocode, write test cases, and write code; then test code. Code was examined for accuracy, flexibility, replicability, and reusability., Key Findings: The pseudocode promoted understanding of the planned algorithm, encouraging discussion and leading to agreement on the case definition algorithms among all team members. The completed SAS code was written for and tested in the Gulf War Era Cohort and Biorepository (GWECB) 4 . This code was adapted and tested in the Million Veteran Program (MVP) 5 . The code was documented for reproducibility and reusability., Significance: Ease of reuse suggests that this method could be used to standardize the application of other case definitions, reducing time and resources spent by each study team. Documentation, code, and test cases are available through the Department of Veterans Affairs (VA) Phenomics catalog 6 ., (Copyright © 2021. Published by Elsevier Inc.)