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Rationale: A common MUC5B gene polymorphism, rs35705950-T, is associated with idiopathic pulmonary fibrosis (IPF), but its role in severe acute respiratory syndrome coronavirus 2 infection and disease severity is unclear. Objectives: To assess whether rs35705950-T confers differential risk for clinical outcomes associated with coronavirus disease (COVID-19) infection among participants in the Million Veteran Program (MVP). Methods: The MUC5B rs35705950-T allele was directly genotyped among MVP participants; clinical events and comorbidities were extracted from the electronic health records. Associations between the incidence or severity of COVID-19 and rs35705950-T were analyzed within each ancestry group in the MVP followed by transancestry meta-analysis. Replication and joint meta-analysis were conducted using summary statistics from the COVID-19 Host Genetics Initiative (HGI). Sensitivity analyses with adjustment for additional covariates (body mass index, Charlson comorbidity index, smoking, asbestosis, rheumatoid arthritis with interstitial lung disease, and IPF) and associations with post-COVID-19 pneumonia were performed in MVP subjects. Measurements and Main Results: The rs35705950-T allele was associated with fewer COVID-19 hospitalizations in transancestry meta-analyses within the MVP (Ncases = 4,325; Ncontrols = 507,640; OR = 0.89 [0.82-0.97]; P = 6.86 × 10-3) and joint meta-analyses with the HGI (Ncases = 13,320; Ncontrols = 1,508,841; OR, 0.90 [0.86-0.95]; P = 8.99 × 10-5). The rs35705950-T allele was not associated with reduced COVID-19 positivity in transancestry meta-analysis within the MVP (Ncases = 19,168/Ncontrols = 492,854; OR, 0.98 [0.95-1.01]; P = 0.06) but was nominally significant (P

BackgroundVeterans often use cannabis for sleep despite limited evidence of its efficacy. Moreover, how sleep disturbances impact cannabis use longitudinally is unclear. We applied a behavioral economic framework to examine whether sleep disturbances and cannabis demand (i.e., relative value) were related risk-factors for future cannabis use and problems.MethodsVeterans deployed post-9/11/2001 who reported past 6-month cannabis use at baseline (n = 126) completed surveys on their sleep disturbances, demand via the Marijuana Purchase Task (MPT), and cannabis use. Mediation analyses using Hayes' PROCESS Macro and zero-inflated negative binomial models tested indirect effects of baseline sleep disturbances on 12-month cannabis use frequency, quantity, and problems via 6-month cannabis demand (i.e., intensity, Omax, Pmax, and breakpoint).ResultsOnly Omax (i.e., maximum expenditure for cannabis) was a significant mediator for 12-month cannabis use quantity and problems when examined concurrently with other demand indices after controlling for covariates. Intensity (i.e., purchase at zero cost) was a significant mediator for 12-month cannabis use frequency when examined concurrently with other demand indices in models controlling for lifetime cannabis use, but not past 30-day use at baseline.ConclusionCannabis demand, specifically intensity and Omax, may help to identify Veterans with sleep disturbances who are at increased risk for escalating their cannabis use. Subsequent research should assess the extent that sleep disturbances impact cannabis demand in the context of withdrawal, which will inform novel prevention and intervention strategies geared toward reducing negative cannabis-related outcomes among Veterans.

Background: Insomnia symptoms are pervasive and persistent in alcohol use disorder (AUD), though little is known about the mechanisms that underlie this association. We previously found that cognitive behavioral therapy for insomnia (CBT‐I) reduced alcohol‐related problems among veterans by improving insomnia severity (NCT03806491). In this planned secondary analysis of the same clinical trial data, we tested negative emotionality as one potential mechanism to explain this effect. Specifically, we tested the change in negative emotionality as a mediator of the association between change in insomnia symptoms and alcohol‐related outcomes (craving, heavy drinking frequency, and alcohol‐related problems). Methods: Participants were 67 veterans in treatment for AUD who also met the criteria for insomnia disorder (91% male, 84% White, average age = 46.3 years). Participants were randomized to five sessions of CBT‐I or a single‐session sleep hygiene control. Assessments occurred at baseline, immediately posttreatment (~6 weeks after baseline), and at 6‐week follow‐up. Measures included the Insomnia Severity Index, Penn Alcohol Craving Scale, Timeline Followback, and Short Inventory of Problems. We created a latent negative emotionality indicator based on five validated and reliable measures of negative emotionality. Results: Contrary to hypotheses, CBT‐I did not improve negative emotionality relative to sleep hygiene control. However, across both treatment conditions, decreases in insomnia symptoms from baseline to posttreatment were associated with concurrent decreases in negative emotionality, which in turn predicted reductions in alcohol craving and heavy drinking. Conclusion: Negative emotionality may help explain links between insomnia symptoms and alcohol‐related outcomes. [ABSTRACT FROM AUTHOR]

Background: Older adults with heart failure are at elevated risk of Alzheimer's disease and related dementias (AD/ADRD). Research suggests that insomnia and depressive episodes contribute somewhat dissociable impacts on risk for AD/ADRD in this patient population, although the temporal ordering of effects is unknown. Objective: This study examined time to dementia diagnosis among patients with comorbid insomnia and/or depressive episodes in an epidemiological sample. Methods: Secondary data analyses were conducted using a cohort study of 203,819 Veterans with a primary admission diagnosis of heart failure in 129 VA Medical Centers. Results: Patients with diagnoses of both insomnia and depressive episodes had the shortest time to a dementia diagnosis at both 1-year (Hazard ratio = 1.43, 95% CI [1.36, 1.51]) and 3-year follow-up time points (Hazard ratio = 1.40, 95% CI [1.34, 1.47]) versus patients with one or neither comorbidity. Conclusions: Individuals with both comorbidities had the shortest time to dementia onset. Screening for these comorbidities may help to identify patients at elevated risk of dementia who could benefit from enhanced monitoring or early intervention strategies for more rapid detection and management of dementia symptoms. [ABSTRACT FROM AUTHOR]

Bitterness from phenylthiocarbamide and 6-n-propylthiouracil (PROP) varies with polymorphisms in the TAS2R38 gene. Three SNPs form two common (AVI, PAV) and four rare haplotypes (AAI, AAV, PVI, and PAI). AVI homozygotes exhibit higher detection thresholds and lower suprathreshold bitterness for PROP compared to PAV homozygotes and heterozygotes, and these differences may influence alcohol and vegetable intake. Within a diplotype, substantial variation in suprathreshold bitterness persists, and some AVI homozygotes report moderate bitterness at high concentrations. A second receptor encoded by a gene containing a functional polymorphism may explain this. Early work has suggested that PROP might activate TAS2R4 in vitro, but later work did not replicate this. Here, we identify three TAS2R4 SNPs that result in three diplotypes—SLN/SLN, FVS/SLN, and FVS/FVS—which make up 25.1%, 44.9%, and 23.9% of our sample. These TAS2R4 haplotypes show minimal linkage disequilibrium with TAS2R38, so we examined the suprathreshold bitterness as a function of both. The participants (n = 243) rated five PROP concentrations in duplicate, interleaved with other stimuli. As expected, the TAS2R38 haplotypes explained ~29% (p < 0.0001) of the variation in the bitterness ratings, with substantial variation within the haplotypes (AVI/AVI, PAV/AVI, and PAV/PAV). Notably, the TAS2R4 diplotypes (independent of the TAS2R38 haplotypes) explained ~7–8% of the variation in the bitterness ratings (p = 0.0001). Given this, we revisited if PROP could activate heterologously expressed TAS2R4 in HEK293T cells, and calcium imaging indicated 3 mM PROP is a weak TAS2R4 agonist. In sum, our data are consistent with the second receptor hypothesis and may explain the recovery of the PROP tasting phenotype in some AVI homozygotes; further, this finding may potentially help explain the conflicting results on the TAS2R38 diplotype and food intake. [ABSTRACT FROM AUTHOR]

This randomized clinical trial assesses the efficacy of cognitive behavioral therapy for insomnia in veterans receiving treatment for alcohol use disorder. Key Points: Question: Is cognitive behavioral therapy for insomnia (CBT-I) feasible and efficacious early in treatment for alcohol use disorder, and if so, does it affect alcohol use? Findings: In this randomized clinical trial involving veterans with insomnia who were in treatment for alcohol use disorder, CBT-I was associated with greater reductions in insomnia symptoms and alcohol-related problems over time than a single session of instruction about sleep hygiene. No group differences emerged for abstinence or heavy-drinking frequency. Meaning: Long-term abstinence may not be required to derive benefit from CBT-I, which is feasible early in alcohol use disorder treatment and may reduce alcohol-related harm. Importance: Three of 4 adults in treatment for alcohol use disorder (AUD) report symptoms of insomnia. Yet the first-line treatment for insomnia (cognitive behavioral therapy for insomnia, CBT-I) is often delayed until abstinence is established. Objective: To test the feasibility, acceptability, and preliminary efficacy of CBT-I among veterans early in their AUD treatment and to examine improvement in insomnia as a mechanism for improvement in alcohol use outcomes. Design, Setting, and Participants: For this randomized clinical trial, participants were recruited through the Addictions Treatment Program at a Veterans Health Administration hospital between 2019 and 2022. Patients in treatment for AUD were eligible if they met criteria for insomnia disorder and reported alcohol use in the past 2 months at baseline. Follow-up visits occurred posttreatment and at 6 weeks. Interventions: Participants were randomly assigned to receive 5 weekly sessions of CBT-I or a single session about sleep hygiene (control). Participants were asked to complete sleep diaries for 7 days at each assessment. Main Outcomes and Measures: Primary outcomes included posttreatment insomnia severity (assessed using the Insomnia Severity Index) and follow-up frequency of any drinking and heavy drinking (4 drinks for women, ≥5 drinks for men; number of days via Timeline Followback) and alcohol-related problems (Short Inventory of Problems). Posttreatment insomnia severity was tested as a mediator of CBT-I effects on alcohol use outcomes at the 6-week follow-up. Results: The study cohort included 67 veterans with a mean (SD) age of 46.3 years (11.8); 61 (91%) were male and 6 (9%) female. The CBT-I group included 32 participants, and the sleep hygiene control group 35 participants. Of those randomized, 59 (88%) provided posttreatment or follow-up data (31 CBT-I, 28 sleep hygiene). Relative to sleep hygiene, CBT-I participants reported greater decreases in insomnia severity at posttreatment (group × time interaction: −3.70; 95% CI, −6.79 to −0.61) and follow-up (−3.34; 95% CI, −6.46 to −0.23) and greater improvements in sleep efficiency (posttreatment, 8.31; 95% CI, 1.35 to 15.26; follow-up, 18.03; 95% CI, 10.46 to 25.60). They also reported greater decreases in alcohol problems at follow-up (group × time interaction: −0.84; 95% CI, −1.66 to −0.02), and this effect was mediated by posttreatment change in insomnia severity. No group differences emerged for abstinence or heavy-drinking frequency. Conclusions and Relevance: In this randomized clinical trial, CBT-I outperformed sleep hygiene in reducing insomnia symptoms and alcohol-related problems over time but had no effect on frequency of heavy drinking. CBT-I should be considered a first-line treatment for insomnia, regardless of abstinence. Trial Registration: ClinicalTrials.gov Identifier: NCT03806491 [ABSTRACT FROM AUTHOR]

Rationale: A common MUC5B gene polymorphism, rs35705950-T, is associated with idiopathic pulmonary fibrosis (IPF), but its role in severe acute respiratory syndrome coronavirus 2 infection and disease severity is unclear. Objectives: To assess whether rs35705950-T confers differential risk for clinical outcomes associated with coronavirus disease (COVID-19) infection among participants in the Million Veteran Program (MVP). Methods: The MUC5B rs35705950-T allele was directly genotyped among MVP participants; clinical events and comorbidities were extracted from the electronic health records. Associations between the incidence or severity of COVID-19 and rs35705950-T were analyzed within each ancestry group in the MVP followed by transancestry meta-analysis. Replication and joint meta-analysis were conducted using summary statistics from the COVID-19 Host Genetics Initiative (HGI). Sensitivity analyses with adjustment for additional covariates (body mass index, Charlson comorbidity index, smoking, asbestosis, rheumatoid arthritis with interstitial lung disease, and IPF) and associations with post-COVID-19 pneumonia were performed in MVP subjects. Measurements and Main Results: The rs35705950-T allele was associated with fewer COVID-19 hospitalizations in transancestry meta-analyses within the MVP (Ncases = 4,325; Ncontrols = 507,640; OR = 0.89 [0.82-0.97]; P = 6.86 × 10-3) and joint meta-analyses with the HGI (Ncases = 13,320; Ncontrols = 1,508,841; OR, 0.90 [0.86-0.95]; P = 8.99 × 10-5). The rs35705950-T allele was not associated with reduced COVID-19 positivity in transancestry meta-analysis within the MVP (Ncases = 19,168/Ncontrols = 492,854; OR, 0.98 [0.95-1.01]; P = 0.06) but was nominally significant (P < 0.05) in the joint meta-analysis with the HGI (Ncases = 44,820; Ncontrols = 1,775,827; OR, 0.97 [0.95-1.00]; P = 0.03). Associations were not observed with severe outcomes or mortality. Among individuals of European ancestry in the MVP, rs35705950-T was associated with fewer post-COVID-19 pneumonia events (OR, 0.82 [0.72-0.93]; P = 0.001). Conclusions: The MUC5B variant rs35705950-T may confer protection in COVID-19 hospitalizations. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 has caused symptomatic COVID-19 and widespread death across the globe. We sought to determine genetic variants contributing to COVID-19 susceptibility and hospitalization in a large biobank linked to a national United States health system. We identified 19,168 (3.7%) lab-confirmed COVID-19 cases among Million Veteran Program participants between March 1, 2020, and February 2, 2021, including 11,778 Whites, 4,893 Blacks, and 2,497 Hispanics. A multi-population genome-wide association study (GWAS) for COVID-19 outcomes identified four independent genetic variants (rs8176719, rs73062389, rs60870724, and rs73910904) contributing to COVID-19 positivity, including one novel locus found exclusively among Hispanics. We replicated eight of nine previously reported genetic associations at an alpha of 0.05 in at least one population-specific or the multi-population meta-analysis for one of the four MVP COVID-19 outcomes. We used rs8176719 and three additional variants to accurately infer ABO blood types. We found that A, AB, and B blood types were associated with testing positive for COVID-19 compared with O blood type with the highest risk for the A blood group. We did not observe any genome-wide significant associations for COVID-19 severity outcomes among those testing positive. Our study replicates prior GWAS findings associated with testing positive for COVID-19 among mostly White samples and extends findings at three loci to Black and Hispanic individuals. We also report a new locus among Hispanics requiring further investigation. These findings may aid in the identification of novel therapeutic agents to decrease the morbidity and mortality of COVID-19 across all major ancestral populations. [ABSTRACT FROM AUTHOR]

This study explores the neurobiological underpinnings of alcohol use disorder (AUD) by integrating bulk and single-cell transcriptomic data from humans, primates, and mice across three brain regions associated with addiction (i.e., prefrontal cortex (PFC), nucleus accumbens (NAc), and central amygdala (CeA)). We compared AUD RNA expression and cell-type abundance from 92 human brain to data from 53 primates and 90 mice engaged in diverse alcohol use paradigms. The findings revealed significant and reproducible correlations between human AUD and mammalian models of alcohol use that vary by tissue, species, and behavioral paradigm. The strongest correlations occurred between primate and mouse models of binge drinking (i.e., high drinking in the dark). Certain primate models demonstrated that the brain RNA correlations with human alcohol use disorder (AUD) were approximately 40% as strong as the correlations observed within human samples themselves. By integrating single-cell transcriptomic data, this study observed decreased oligodendrocyte proportions in the PFC and NAc of human AUD with similar trends in animal models. Gene co-expression network analyses revealed conserved systems associated with human AUD and animal models of heavy/binge alcohol consumption. Gene co-expression networks were enriched for pathways related to inflammation, myelination, and synaptic plasticity and the genes within them accounted for ~20% of the heritability in human alcohol consumption. Identified hub genes were associated with relevant traits (e.g., impulsivity, motivation) in humans and mice. This study sheds light on conserved biological entities underlying AUD and chronic alcohol use, providing insights into the cellular, genetic, and neuromolecular basis across species., Competing Interests: Conflicts: The authors have no conflicts to declare.

Importance: Sickle cell trait (SCT), defined as the presence of 1 hemoglobin beta sickle allele (rs334-T) and 1 normal beta allele, is prevalent in millions of people in the US, particularly in individuals of African and Hispanic ancestry. However, the association of SCT with COVID-19 is unclear., Objective: To assess the association of SCT with the prepandemic health conditions in participants of the Million Veteran Program (MVP) and to assess the severity and sequelae of COVID-19., Design, Setting, and Participants: COVID-19 clinical data include 2729 persons with SCT, of whom 353 had COVID-19, and 129 848 SCT-negative individuals, of whom 13 488 had COVID-19. Associations between SCT and COVID-19 outcomes were examined using firth regression. Analyses were performed by ancestry and adjusted for sex, age, age squared, and ancestral principal components to account for population stratification. Data for the study were collected between March 2020 and February 2021., Exposures: The hemoglobin beta S (HbS) allele (rs334-T)., Main Outcomes and Measures: This study evaluated 4 COVID-19 outcomes derived from the World Health Organization severity scale and phenotypes derived from International Classification of Diseases codes in the electronic health records., Results: Of the 132 577 MVP participants with COVID-19 data, mean (SD) age at the index date was 64.8 (13.1) years. Sickle cell trait was present in 7.8% of individuals of African ancestry and associated with a history of chronic kidney disease, diabetic kidney disease, hypertensive kidney disease, pulmonary embolism, and cerebrovascular disease. Among the 4 clinical outcomes of COVID-19, SCT was associated with an increased COVID-19 mortality in individuals of African ancestry (n = 3749; odds ratio, 1.77; 95% CI, 1.13 to 2.77; P = .01). In the 60 days following COVID-19, SCT was associated with an increased incidence of acute kidney failure. A counterfactual mediation framework estimated that on average, 20.7% (95% CI, -3.8% to 56.0%) of the total effect of SCT on COVID-19 fatalities was due to acute kidney failure., Conclusions and Relevance: In this genetic association study, SCT was associated with preexisting kidney comorbidities, increased COVID-19 mortality, and kidney morbidity.