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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.

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.

IntroductionAs many as 74% of veterans with alcohol use disorders (AUDS) report symptoms of insomnia. Insomnia represents a barrier to alcohol treatment because insomnia symptoms (1) may lead to relapse among those who use alcohol to help them sleep and may negatively impact (2) executive functions and (3) emotion regulation skills. Cognitive-behavioural therapy for insomnia (CBT-I) is an efficacious first-line treatment for insomnia; however, no research has examined the impact of CBT-I on individuals' response to alcohol treatment. In the Sleep and Alcohol for Veterans (Project SAVE) randomised controlled trial, we hypothesise that CBT-I will enhance the efficacy of alcohol treatment among Veterans with insomnia by enhancing their abilities to attend to treatment, regulate emotions and initiate sleep without alcohol.Methods and analysisEighty Veterans enrolled in alcohol treatment at the Veterans Administration (VA) hospital will be randomly assigned to receive either CBT-I or single-session sleep hygiene (SH) education. Individuals will be eligible to participate if they meet Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for moderate to severe AUD and Insomnia Disorder of at least 1-month duration. Participants will complete assessments at baseline, post-treatment and 6-week follow-up. Preliminary process outcomes include retention/recruitment rates and treatment satisfaction (feasibility and acceptability, respectively). Primary outcomes are insomnia severity, percentage of heavy-drinking days and alcohol-related problems. We will assess a variety of secondary clinical and mechanistic outcomes (eg, post-traumatic stress disorder (PTSD) symptoms, attention and working memory).Ethics and disseminationEthics approval was obtained in October 2018. Data collection began in July 2019 and is planned for completion by July 2021. Trial results will be disseminated at local and national conferences, in peer-reviewed publications and through media outlets, as available. Results will also be shared with interested participants and clinical collaborators at the end of the trial.Trial registration numberclinicaltrials.gov identifier NCT03806491 (pre-results).

BackgroundAlcoholism is a multifactorial disorder influenced by multiple gene loci, each with small effect. Studies suggest shared genetic influences across DSM-IV alcohol dependence symptoms, but shared effects across DSM-5 alcohol use disorder remains unknown. We aimed to test the assumption of genetic homogeneity across the 11 criteria of DSM-5 alcohol use disorder (AUD).MethodsData from 2596 alcohol using individuals of European ancestry from the Study of Addiction: Genetics and Environment were used to examine the genomewide SNP-heritability (h2SNP) and SNP-covariance (rGSNP) between 11 DSM-5 AUD symptoms. Phenotypic relationships between symptoms were examined to confirm an underlying liability of AUD and the SNP-heritability of the observed latent trait and the co-heritabilityamong AUD symptoms was assessed using Genomic-Relatedness-Matrix-Restricted-Maximum-Likelihood. Genetic covariance among symptoms was examined using factor analysis.ResultsPhenotypic relationships confirmed a unidimensional underlying liability to AUD. Factor and parallel analyses of the observed genetic variance/covariance provided evidence of genetic homogeneity. Additive genetic effects on DSM-5 AUD symptoms varied from 0.10 to 0.37 and largely overlapped (rG-SNP across symptoms ranged from 0.49 - 0.92). The additive genetic effect on the DSM-5 AUD factor was 0.36, 0.14 for DSM-5 AUD diagnosis, and was 0.22 for DSM-5 AUD severity.ConclusionsCommon genetic variants influence DSM-5 AUD symptoms. Despite evidence for a common AUD factor, the evidence of only partially overlapping genetic effects across AUD symptoms further substantiates the need to simultaneously model common and symptom-specific genetic effects in molecular genetic studies in order to best characterize the genetic liability.

ObjectiveIndependent lines of research have documented links between psychiatric symptoms and poor sleep quality, psychiatric symptoms and alcohol use, and alcohol use and poor sleep quality. The current study examined the synergistic effect of poor sleep quality and psychiatric symptoms on alcohol-related consequences in heavy-drinking young adults.MethodMatriculating college students reporting at least one heavy drinking episode over the first nine weeks of the semester (N=385, 52% female) were categorized as experiencing 'good' (n=280) versus 'poor' sleep quality (n=105) and screening 'positive' (n=203) or 'negative' (n=182) for a psychiatric disorder. Sleep quality was assessed using the Pittsburgh Sleep Quality Index; psychiatric diagnosis was assessed using the Psychiatric Diagnostic Screening Questionnaire; and alcohol-related consequences were assessed using the Brief Young Adult Alcohol Consequences Questionnaire. General linear models were used to examine the main effects and interaction between sleep quality and psychiatric symptoms on alcohol-related consequences.ResultsSleep quality moderated the association between psychiatric screen and alcohol-related consequences among heavy-drinking college students, such that psychiatric symptoms were associated with more alcohol-related consequences in the context of poor sleep quality.ConclusionsThe combination of poor sleep quality and psychiatric symptoms is associated with increased alcohol-related consequences among heavy-drinking college students. Given the significant interaction between these symptoms, healthcare providers are encouraged to screen for the presence of sleep and psychiatric disorders among heavy-drinking young adults and to provide empirically-supported treatments as appropriate.

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]

Study objectivesTo examine whether differences exist in self-reported sleep patterns and self-reported alcohol use for first-semester college students who do or do not report drinking during the last 6 months (mo) of high school.MethodsParticipants were 878 first-year college students. Students completed a survey in late May/early June about alcohol use and consequences, during the last 6 mo of high school; they later completed a daily record of sleep behavior and alcohol use across the first 9 weeks of the first semester of college. High school drinking status (past 6 mo) was classified as positive (HS-6 mo+) or negative (HS-6mo-) based on any indication of drinking on the May/June survey. Collegiate drinking was determined from first-semester daily diary alcohol reports as non-drinkers (0 reported drinks), drinkers (one or fewer heavy episodic drinking episodes (HED)), and drinkers reporting more than one HED episode. Sleep patterns were compared for non-drinkers, drinkers, and HED with no high school drinking history (HS-6mo-/HED). In addition, a separate analysis compared sleep patterns for college HED with (HS-6mo+/HED) and without (HS-6mo-/HED) high school self-reported alcohol use.ResultsIncreased alcohol consumption in the first semester of college was associated with later bedtimes and rise times. We found no association of high school alcohol use and sleep in those with collegiate HED.ConclusionsLater sleep timing in those with greater alcohol use, supports a connection between sleep patterns and alcohol use. Such an early appearance of this connection may herald the development of alcohol use disorder in some individuals.

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]

AimsTo evaluate the associations of treatment and an additive genetic efficacy score (AGES) based on dopamine functional polymorphisms with time to first smoking lapse and point prevalence abstinence at end of treatment among participants enrolled into two randomized clinical trials of smoking cessation therapies.DesignDouble-blind pharmacogenetic efficacy trials randomizing participants to active or placebo bupropion. Study 1 also randomized participants to cognitive-behavioral smoking cessation treatment (CBT) or this treatment with CBT for depression. Study 2 provided standardized behavioural support.SettingTwo hospital-affiliated clinics (study 1), and two university-affiliated clinics (study 2).ParticipantsA total of 792 self-identified white treatment-seeking smokers aged ≥18 years smoking ≥10 cigarettes per day over the last year.MeasurementsAge, gender, Fagerström Test for Nicotine Dependence, dopamine pathway genotypes (rs1800497 [ANKK1 E713K], rs4680 [COMT V158M], DRD4 exon 3 variable number of tandem repeats polymorphism [DRD4 VNTR], SLC6A3,3' VNTR) analyzed both separately and as part of an AGES, time to first lapse and point prevalence abstinence at end of treatment.FindingsSignificant associations of the AGES (hazard ratio [HR] = 1.10, 95% confidence interval [CI] = 1.06-1.14, P = 0.009) and of the DRD4 VNTR (HR = 1.29, 95% CI = 1.17-1.41, P = 0.0073) were observed with time to first lapse. A significant AGES by pharmacotherapy interaction was observed (β standard error = -0.18 [0.07], P = 0.016), such that AGES predicted risk for time to first lapse only for individuals randomized to placebo.ConclusionsA score based on functional polymorphisms relating to dopamine pathways appears to predict lapse to smoking following a quit attempt, and the association is mitigated in smokers using bupropion.

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]

There is growing evidence that a functional polymorphism in the serotonin transporter gene (5-HTTLPR) moderates the impact of negative life events (e.g., childhood abuse) on the development of depression. However, it is unclear whether the gene x environment interaction predicts suicide attempts specifically. In addition, previous studies have not examined different forms of childhood abuse separately. In the current study, we found that 5-HTTLPR genotype moderated the link between childhood physical and sexual, but not emotional, abuse and adult psychiatric inpatients' histories of suicide attempts.