A case-control study: epigenetic age acceleration in psoriasis.

Psoriasis (PsO) is a chronic inflammatory skin condition, often accompanied by psoriatic arthritis (PsA) and linked to various comorbidities and increased mortality rates. This study aimed to explore the relationship between PsO and accelerated biological aging, specifically focusing on epigenetic DNA methylation clocks. Using a matched case-control design, 20 PsO cases were selected along with age, race, and sex-matched 20 controls without PsO from the Skin Disease Biorepository at Brown Dermatology, Inc, Providence, Rhode Island. Blood samples retrieved from both groups were analyzed for DNA methylation, and epigenetic ages were calculated using DNA methylation clocks, including Horvath, Hannum, Pheno, SkinBlood, and Grim ages. Generalized estimation equations were employed to test the differences in epigenetic and chronological ages between PsO cases and controls, as well as within various subgroups in comparison to their respective controls. There were no statistically significant differences in epigenetic ages between PsO cases and controls. However, notably, PsO cases with PsA demonstrated an accelerated PhenoAge, compared to their matched controls. This study represents a pioneering investigation into the potential link between PsO and epigenetic aging, shedding light on the possibility of accelerated epigenetic aging in PsA, possibly associated with heightened inflammatory burden. These findings emphasize the systemic impact of PsA on the aging process, prompting the need for deeper exploration into autoimmune pathways, inflammation, and epigenetic modifications underlying PsO pathogenesis and aging mechanisms. Larger-scale studies with diverse populations are imperative to discern PsO subgroups experiencing accelerated biological aging and decipher the intricate interplay between PsO, inflammation, and aging pathways.

Maternal smoking during pregnancy is associated with DNA methylation in early adolescence: A sibling comparison design.

Maternal smoking during pregnancy (MSDP) may impact offspring biological (e.g., deoxyribonucleic acid methylation [DNAm]) and behavioral (e.g., attention-deficit/hyperactivity disorder hyperactive/impulsive [ADHD-HI] symptoms) development. There has been consistency in findings of differential methylation in global DNAm, and the specific genes AHRR, CYP1A1, CNTNAP2, MYO1G, and GFI1 in relation to MSDP. The current study aims to (a) replicate the associations of MSDP and DNAm in prior literature in middle childhood-adolescence (cross-sectionally) using a sibling-comparison design where siblings were discordant for MSDP (n = 328 families; Mage Sibling 1 = 13.02; Sibling 2 = 10.20), adjusting for prenatal and postnatal covariates in order to isolate the MSDP exposure on DNAm. We also (b) cross-sectionally explored the role of DNAm in the most robust MSDP-ADHD associations (i.e., with ADHD-HI) previously found in this sample. We quantified smoking exposure severity for each sibling reflecting time and quantity of MSDP, centered relative to the sibling pair's average (i.e., within-family centered, indicating child-specific effects attributable MSDP exposure) and controlling for the sibling average MSDP (i.e., between-family component, indicating familial confounding related to MSDP). We found that child-specific MSDP was associated with global DNAm, and CNTNAP2, CYP1A1, and MYO1G methylation after covariate adjustment, corroborating emerging evidence for a potentially causal pathway between MSDP and DNAm. There was some evidence that child-specific CNTNAP2 and MYO1G methylation partially explained associations between MSDP and ADHD-HI symptoms, though only on one measure (of two). Future studies focused on replication of these findings in a longitudinal genetic design could further solidify the associations found in the current study. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

A MUC5B Gene Polymorphism, rs35705950-T, Confers Protective Effects Against COVID-19 Hospitalization but Not Severe Disease or Mortality.

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.

New Antipsychotic Prescribing Continued into Skilled Nursing Facilities Following a Heart Failure Hospitalization: a Retrospective Cohort Study.

BACKGROUND: Multimorbidity and polypharmacy are common among individuals hospitalized for heart failure (HF). Initiating high-risk medications such as antipsychotics may increase the risk of poor clinical outcomes, especially if these medications are continued unnecessarily into skilled nursing facilities (SNFs) after hospital discharge. OBJECTIVE: Examine how often older adults hospitalized with HF were initiated on antipsychotics and characteristics associated with antipsychotic continuation into SNFs after hospital discharge. DESIGN: Retrospective cohort. PARTICIPANTS: Veterans without prior outpatient antipsychotic use, who were hospitalized with HF between October 1, 2010, and September 30, 2015, and were subsequently discharged to a SNF. MAIN MEASURES: Demographics, clinical conditions, prior healthcare utilization, and antipsychotic use data were ascertained from Veterans Administration records, Minimum Data Set assessments, and Medicare claims. The outcome of interest was continuation of antipsychotics into SNFs after hospital discharge. KEY RESULTS: Among 18,008 Veterans, antipsychotics were newly prescribed for 1931 (10.7%) Veterans during the index hospitalization. Among new antipsychotic users, 415 (21.5%) continued antipsychotics in skilled nursing facilities after discharge. Dementia (adjusted OR (aOR) 1.48, 95% CI 1.11-1.98), psychosis (aOR 1.62, 95% CI 1.11-2.38), proportion of inpatient days with antipsychotic use (aOR 1.08, 95% CI 1.07-1.09, per 10% increase), inpatient use of only typical (aOR 0.47, 95% CI 0.30-0.72) or parenteral antipsychotics (aOR 0.39, 95% CI 0.20-0.78), and the day of hospital admission that antipsychotics were started (day 0-4 aOR 0.36, 95% CI 0.23-0.56; day 5-7 aOR 0.54, 95% CI 0.35-0.84 (reference: day > 7 of hospital admission)) were significant predictors of continuing antipsychotics into SNFs after hospital discharge. CONCLUSIONS: Antipsychotics are initiated fairly often during HF admissions and are commonly continued into SNFs after discharge. Hospital providers should review antipsychotic indications and doses throughout admission and communicate a clear plan to SNFs if antipsychotics are continued after discharge.

Multi-Polygenic Analysis of Nicotine Dependence in Individuals of European Ancestry.

INTRODUCTION: Heritability estimates of nicotine dependence (ND) range from 40% to 70%, but discovery GWAS of ND are underpowered and have limited predictive utility. In this work, we leverage genetically correlated traits and diseases to increase the accuracy of polygenic risk prediction. METHODS: We employed a multi-trait model using summary statistic-based best linear unbiased predictors (SBLUP) of genetic correlates of DSM-IV diagnosis of ND in 6394 individuals of European Ancestry (prevalence = 45.3%, %female = 46.8%, µâ€Šage = 40.08 [s.d. = 10.43]) and 3061 individuals from a nationally-representative sample with Fagerström Test for Nicotine Dependence symptom count (FTND; 51.32% female, mean age = 28.9 [s.d. = 1.70]). Polygenic predictors were derived from GWASs known to be phenotypically and genetically correlated with ND (i.e., Cigarettes per Day [CPD], the Alcohol Use Disorders Identification Test [AUDIT-Consumption and AUDIT-Problems], Neuroticism, Depression, Schizophrenia, Educational Attainment, Body Mass Index [BMI], and Self-Perceived Risk-Taking); including Height as a negative control. Analyses controlled for age, gender, study site, and the first 10 ancestral principal components. RESULTS: The multi-trait model accounted for 3.6% of the total trait variance in DSM-IV ND. Educational Attainment (ß = -0.125; 95% CI: [-0.149,-0.101]), CPD (0.071 [0.047,0.095]), and Self-Perceived Risk-Taking (0.051 [0.026,0.075]) were the most robust predictors. PGS effects on FTND were limited. CONCLUSIONS: Risk for ND is not only polygenic, but also pleiotropic. Polygenic effects on ND that are accessible by these traits are limited in size and act additively to explain risk. IMPLICATIONS: These findings enhance our understanding of inherited genetic factors for nicotine dependence. The data show that genome-wide association study (GWAS) findings across pre- and comorbid conditions of smoking are differentially associated with nicotine dependence and that when combined explain significantly more trait variance. These findings underscore the utility of multivariate approaches to understand the validity of polygenic scores for nicotine dependence, especially as the power of GWAS of broadly-defined smoking behaviors increases. Realizing the potential of GWAS to inform complex smoking behaviors will require similar theory-driven models that reflect the myriad of mechanisms that drive individual differences.

Multi-omic and multi-species meta-analyses of nicotine consumption.

Cross-species translational approaches to human genomic analyses are lacking. The present study uses an integrative framework to investigate how genes associated with nicotine use in model organisms contribute to the genetic architecture of human tobacco consumption. First, we created a model organism geneset by collecting results from five animal models of nicotine exposure (RNA expression changes in brain) and then tested the relevance of these genes and flanking genetic variation using genetic data from human cigarettes per day (UK BioBank N = 123,844; all European Ancestry). We tested three hypotheses: (1) DNA variation in, or around, the 'model organism geneset' will contribute to the heritability to human tobacco consumption, (2) that the model organism genes will be enriched for genes associated with human tobacco consumption, and (3) that a polygenic score based off our model organism geneset will predict tobacco consumption in the AddHealth sample (N = 1667; all European Ancestry). Our results suggested that: (1) model organism genes accounted for ~5-36% of the observed SNP-heritability in human tobacco consumption (enrichment: 1.60-31.45), (2) model organism genes, but not negative control genes, were enriched for the gene-based associations (MAGMA, H-MAGMA, SMultiXcan) for human cigarettes per day, and (3) polygenic scores based on our model organism geneset predicted cigarettes per day in an independent sample. Altogether, these findings highlight the advantages of using multiple species evidence to isolate genetic factors to better understand the etiological complexity of tobacco and other nicotine consumption.

Alcohol Consumption among Samoan Adults in 2010: Patterns, Correlates and Health Implications.

AIMS: We aim to describe alcohol consumption and related problems from a nationwide survey in 2010 in Samoa in association with sociodemographic variables as part of an intervention development. METHODS: The sample consisted of 3463 adults, 25-65 years of age. Participants self-reported alcohol consumption in the previous 12 months, patterns of drinking and alcohol-related psychosocial problems. Data about age, census region of residence, highest attained education level, employment, marital status, household assets score and current smoking status were gathered. RESULTS: More than one-third of men, 36.1%, and 4.1% of women consumed alcohol in the past year. There were greater proportions of alcohol users among younger adults, <45 years, in both men and women. Among men, being unemployed and residing outside of rural Savai'i and smoking cigarettes were associated with current alcohol use. Among women, tertiary education and cigarette smoking were strongly associated with alcohol use. Among alcohol consumers, almost 75% of both men and women reported being drunk more than once in the prior month, and 58% of men and 81% of women drank heavily, consuming >4 drinks for women and >5 drinks for men at least once per episode in the prior week. More men than women, 51% versus 26%, felt that alcohol consumption had interfered with their daily life. CONCLUSION: Our analyses identified correlates of alcohol consumption and associated problems that can help guide the development of targeted interventions for different sex and age groups to mitigate the social and physiological harms of alcohol misuse.

CNR1 and FAAH variation and affective states induced by marijuana smoking.

Background: Polymorphisms in cannabinoid receptor type 1 (encoded by CNR1) and fatty acid amide hydrolase (encoded by FAAH) have been associated with cannabis dependence, but it remains unknown whether variation within these genes influences cannabis' acute effects on affect. Objective: Conduct a secondary data analysis study to determine whether previously observed acute effects of tetrahydrocannabinol (THC) on mood was dependent upon variation in CNR1 and FAAH. Methods: A balanced placebo design was used crossing marijuana administration (i.e., 0% THC vs. 2.8% THC) with stimulus expectancy. Participants (N = 118; 64% male) provided DNA and completed the Profile of Mood States questionnaire prior to and after smoking. Haplotypes were constructed from genotyped single nucleotide polymorphisms for CNR1 (rs1049353 and rs806368) and FAAH (rs4141964, rs324420, and rs11576941); rs2023239 (CNR1) and rs6703669 (FAAH) were not part of a phased haplotype block. Analyses tested both main and interaction effects for genotype across CNR1 and FAAH, and drug, and expectancy effects. Results: THC increased levels of POMS Tension-Anxiety and Confusion-Bewilderment over and above the effects of variation in CNR1 and FAAH. Significant drug X genotype/haplotype and expectancy X genotype/haplotype interaction effects were observed for some but not all mood states [e.g., 'C' allele carriers of rs2023239 who received THC had higher levels of Anger-Hostility (ß= 0.29 (0.12), p= .02) compared to those who received placebo]. Conclusion: These preliminary findings suggest individual differences in mood states after using marijuana depend on genetic variation. Such information might be useful in understanding either motivation for use of marijuana and/or risk for associated behaviors.

Cue-elicited increases in incentive salience for marijuana: Craving, demand, and attentional bias.

BACKGROUND: Incentive salience is a multidimensional construct that includes craving, drug value relative to other reinforcers, and implicit motivation such as attentional bias to drug cues. Laboratory cue reactivity (CR) paradigms have been used to evaluate marijuana incentive salience with measures of craving, but not with behavioral economic measures of marijuana demand or implicit attentional processing tasks. METHODS: This within-subjects study used a new CR paradigm to examine multiple dimensions of marijuana's incentive salience and to compare CR-induced increases in craving and demand. Frequent marijuana users (N=93, 34% female) underwent exposure to neutral cues then to lit marijuana cigarettes. Craving, marijuana demand via a marijuana purchase task, and heart rate were assessed after each cue set. A modified Stroop task with cannabis and control words was completed after the marijuana cues as a measure of attentional bias. RESULTS: Relative to neutral cues, marijuana cues significantly increased subjective craving and demand indices of intensity (i.e., drug consumed at $0) and Omax (i.e., peak drug expenditure). Elasticity significantly decreased following marijuana cues, reflecting sustained purchase despite price increases. Craving was correlated with demand indices (r's: 0.23-0.30). Marijuana users displayed significant attentional bias for cannabis-related words after marijuana cues. Cue-elicited increases in intensity were associated with greater attentional bias for marijuana words. CONCLUSIONS: Greater incentive salience indexed by subjective, behavioral economic, and implicit measures was observed after marijuana versus neutral cues, supporting multidimensional assessment. The study highlights the utility of a behavioral economic approach in detecting cue-elicited changes in marijuana incentive salience.

Passive rGE or Developmental Gene-Environment Cascade? An Investigation of the Role of Xenobiotic Metabolism Genes in the Association Between Smoke Exposure During Pregnancy and Child Birth Weight.

There is considerable evidence that smoke exposure during pregnancy (SDP) environmentally influences birth weight after controlling for genetic influences and maternal characteristics. However, maternal smoking during pregnancy-the behavior that leads to smoke exposure during pregnancy-is also genetically-influenced, indicating the potential role of passive gene-environment correlation. An alternative to passive gene-SDP correlation is a cascading effect whereby maternal and child genetic influences are causally linked to prenatal exposures, which then have an 'environmental' effect on the development of the child's biology and behavior. We describe and demonstrate a conceptual framework for disentangling passive rGE from this cascading GE effect using a systems-based polygenic scoring approach comprised of genes shown to be important in the xenobiotic (substances foreign to the body) metabolism pathway. Data were drawn from 5044 families from the Avon Longitudinal Study of Parents and Children with information on maternal SDP, birth weight, and genetic polymorphisms in the xenobiotic pathway. Within a k-fold cross-validation approach (k = 5), we created weighted maternal and child polygenic scores using 18 polymorphisms from 10 genes that have been implicated in the xenobiotic metabolism pathway. Mothers and children shared variation in xenobiotic metabolism genes. Amongst mothers who smoked during pregnancy, neither maternal nor child xenobiotic metabolism polygenic scores were associated with a higher likelihood of smoke exposure during pregnancy, or the severity of smoke exposure during pregnancy (and therefore, neither proposed mechanism was supported), or with child birth weight. SDP was consistently associated with lower child birth weight controlling for the polygenic scores, maternal educational attainment, social class, psychiatric problems, and age. Limitations of the study design and the potential of the framework using other designs are discussed.

Influence of the A118G Polymorphism of the OPRM1 Gene and Exon 3 VNTR Polymorphism of the DRD4 Gene on Cigarette Craving After Alcohol Administration.

INTRODUCTION: The current study examined whether the presence of the G allele of the A118G polymorphism of the OPRM1 gene (rs1799971) and the long allele of exon 3 VNTR polymorphism of the DRD4 gene moderate the effect of alcohol administration on urge to smoke. These polymorphisms have been associated with greater alcohol induced-urge to drink. Urge to drink and alcohol consumption increase urge to smoke. Therefore, these polymorphisms may also sensitize urge to smoke after alcohol consumption. METHODS: Individuals smoking 10-30 cigarettes per day and reporting heavy drinking were recruited from the community. Caucasians (n = 62), 57.3% male, mean age 39.2, took part in a three-session, within-subjects, repeated-measures design study. Participants were administered a placebo, 0.4 g/kg, or 0.8 g/kg dose of alcohol. A118G genotype, exon 3 VNTR genotype, and urge to smoke (baseline and three times after receiving alcohol) were assessed. RESULTS: G allele carriers showed greater urge to smoke across all assessments. Additionally, a significant interaction indicated that G carriers, compared to homozygotes (AA), evinced a significantly greater increase in urge to smoke after high dose alcohol relative to placebo. The interaction between condition, DRD4 polymorphism, and time was not significant. CONCLUSIONS: Presence of G allele of the A118G polymorphism of the OPRM1 gene may lead to greater increases in urge to smoke after a high dose of alcohol. Pharmacotherapies targeted to opiate receptors (eg, naltrexone) may be especially helpful in aiding smoking cessation among G carriers who are heavy drinkers.

Missouri Mothers and Their Children: A Family Study of the Effects of Genetics and the Prenatal Environment.

The Missouri Mothers and Their Children Study (MO-MATCH) was specifically designed to critically investigate prenatal environmental influences on child attention problems and associated learning and cognitive deficits. The project began as a pilot study in 2004 and was formally launched in 2008. Participants in the study were initially identified via the Department of Vital Statistics birth record (BR) database. Interview and lab-based data were obtained from: (1) mothers of Missouri-born children (born 1998-2005), who smoked during one pregnancy but not during another pregnancy; (2) biological fathers when available; and (3) the children (i.e., full sibling pairs discordant for exposure to maternal smoking during pregnancy (SDP). This within-mother, between-pregnancy contrast provides the best possible methodological control for many stable maternal and familial confounding factors (e.g., heritable and socio-demographic characteristics of the mother that predict increased probability of SDP). It also controls for differences between mothers who do and do not smoke during pregnancy, and their partners, that might otherwise artifactually create, or alternatively mask, associations between SDP and child outcomes. Such a design will therefore provide opportunities to determine less biased effect sizes while also allowing us to investigate (on a preliminary basis) the possible contribution of paternal or other second-hand smoke exposure during the pre, peri, and postnatal periods to offspring outcome. This protocol has developed a cohort that can be followed longitudinally through periods typically associated with increased externalizing symptoms and substance used initiation.

Genetic influences on delay discounting in smokers: examination of a priori candidates and exploration of dopamine-related haplotypes.

RATIONALE: Delay discounting is a behavioral economic index of impulsivity that reflects a person's relative preference for small immediate rewards versus larger delayed rewards. Elevated delay discounting is robustly linked to addictive disorders and has been increasingly investigated as a viable endophenotype for genetic influences on addiction. OBJECTIVE: The aim of this study is to examine associations between delay discounting and two a priori loci, rs4680 in COMT and rs1800497 in ANKK1, and three exploratory haplotypes proximal to rs1800497 in a sample of daily smokers. METHODS: Participants were 713 (60.2 % male) daily smokers of European ancestry who completed a delay discounting assessment and provided a DNA sample. RESULTS: Significant associations were detected between greater discounting of medium magnitude rewards (~$55) and the G allele of rs4680, as well as the T allele of rs1800497. Exploratory haplotype analyses identified two haplotypes (rs1160467/rs1800497; rs6277/rs1079597) significantly associated with delay discounting rates. However, the rs1160467/rs1800497 haplotype associations appeared to be entirely attributable to variation in rs1800497, suggesting that the association of rs1800497 with discounting is best understood at the individual SNP level. Similarly, the rs6277/rs1079597 haplotype findings suggested that the association was specific to rs1079597. CONCLUSIONS: This study provides further evidence that rs4680 and rs1800497 genotypes are significantly associated with delay discounting preferences and does so among smokers for the first time. The study also provides evidence of specificity for the rs1800497 association and identifies a novel locus, rs1079597, as a genetic contributor to higher delay discounting rates.

Marijuana's acute effects on cognitive bias for affective and marijuana cues.

Marijuana produces acute increases in positive subjective effects and decreased reactivity to negative affective stimuli, though may also acutely induce anxiety. Implicit attentional and evaluative processes may explicate marijuana's ability to acutely increase positive and negative emotions. This within-subjects study examined whether smoked marijuana with 2.7-3.0% delta-9-tetrahydrocannabinol (THC), relative to placebo, acutely changed attentional processing of rewarding and negative affective stimuli as well as marijuana-specific stimuli. On 2 separate days, regular marijuana users (N = 89) smoked placebo or active THC cigarette and completed subjective ratings of mood, intoxication, urge to smoke marijuana, and 2 experimental tasks: pleasantness rating (response latency and perceived pleasantness of affective and marijuana-related stimuli) and emotional Stroop (attentional bias to affective stimuli). On the pleasantness rating task, active marijuana increased response latency to negatively valenced and marijuana-related (vs. neutral) visual stimuli, beyond a general slowing of response. Active marijuana also increased pleasantness ratings of marijuana images, although to a lesser extent than placebo due to reduced marijuana urge after smoking. Overall, active marijuana did not acutely change processing of positive emotional stimuli. There was no evidence of attentional bias to affective word stimuli on the emotional Stroop task with the exception of attentional bias to positive word stimuli in the subgroup of marijuana users with cannabis dependence. Marijuana may increase allocation of attentional resources toward marijuana-specific and negatively valenced visual stimuli without altering processing of positively valenced stimuli. Marijuana-specific cues may be more attractive with higher levels of marijuana craving and less wanted with low craving levels.

Examining the role of common genetic variants on alcohol, tobacco, cannabis and illicit drug dependence: genetics of vulnerability to drug dependence.

BACKGROUND AND AIMS: Twin and family studies suggest that genetic influences are shared across substances of abuse. However, despite evidence of heritability, genome-wide association and candidate gene studies have indicated numerous markers of limited effects, suggesting that much of the heritability remains missing. We estimated (1) the aggregate effect of common single nucleotide polymorphisms (SNPs) on multiple indicators of comorbid drug problems that are typically employed across community and population-based samples, and (2) the genetic covariance across these measures. PARTICIPANTS: A total of 2596 unrelated subjects from the Study of Addiction: Genetics and Environment provided information on alcohol, tobacco, cocaine, cannabis and other illicit substance dependence. Phenotypic measures included: (1) a factor score based on DSM-IV drug dependence diagnoses (DD), (2) a factor score based on problem use (PU; i.e. 1+ DSM-IV symptoms) and (3) dependence vulnerability (DV; a ratio of DSM-IV symptoms to the number of substances used). FINDINGS: Univariate and bivariate genome-wide complex trait analyses of this selected sample indicated that common SNPs explained 25-36% of the variance across measures, with DD and DV having the largest effects [h(2) SNP (standard error) = 0.36 (0.13) and 0.33 (0.13), respectively; PU = 0.25 (0.13)]. Genetic effects were shared across the three phenotypic measures of comorbid drug problems [rDD-PU = 0.92 (0.08), rDD-DV = 0.97 (0.08) and rPU-DV = 0.96 (0.07)]. CONCLUSION: At least 20% of the variance in the generalized vulnerability to substance dependence is attributable to common single nucleotide polymorphisms. The additive effect of common single nucleotide polymorphisms is shared across important indicators of comorbid drug problems.

Acute effects of low and high dose alcohol on smoking lapse behavior in a laboratory analogue task.

RATIONALE: Smoking lapses (i.e., returns to smoking after quitting) often occur following alcohol consumption with observational data suggesting greater quantities of alcohol lead to greater risk. However, a causal dose-dependent effect of alcohol consumption on smoking lapse behavior has not been established, and the mechanisms that might account for such an effect have not been tested. OBJECTIVES: In a within-subjects design, we examined the effects of low- (0.4 g/kg) and high-dose (0.8 g/kg) alcohol, relative to placebo, on smokers' ability to resist initiating smoking after acute smoking abstinence. METHODS: Participants were 100 heavy alcohol drinkers, smoking 10-30 cigarettes per day. Across three separate days, participants consumed placebo, low-dose, or high-dose alcohol following 3 h of smoking abstinence and, 35 min later, were offered the opportunity to smoke while resisting smoking was monetarily reinforced proportional to the amount of time delayed. RESULTS: Consistent with a dose-response effect, participants smoked 3.35 min (95 % confidence intervals (CI) [-7.09, 0.40], p = .08) earlier following low-dose alcohol and 6.36 min (95 % CI [-9.99, -2.73], p = .0006) earlier following high-dose alcohol compared to drinking a placebo beverage. Effects of dose on smoking behavior were partially mediated by increases in urge to smoke. There was no evidence that alcohol's effects on urge to smoke or ability to resist smoking were mediated through its stimulating or sedating effects. CONCLUSIONS: Alcohol can reduce the ability to resist smoking in a dose-dependent fashion, in part, due to its effect on increasing the intensity of smoking urges.

Influence of a dopamine pathway additive genetic efficacy score on smoking cessation: results from two randomized clinical trials of bupropion.

AIMS: To 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. DESIGN: Double-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. SETTING: Two hospital-affiliated clinics (study 1), and two university-affiliated clinics (study 2). PARTICIPANTS: A total of 792 self-identified white treatment-seeking smokers aged ≥18 years smoking ≥10 cigarettes per day over the last year. MEASUREMENTS: Age, 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. FINDINGS: Significant 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 (ß 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. CONCLUSIONS: A 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.

The epigenetics of maternal cigarette smoking during pregnancy and effects on child development.

The period of in utero development is one of the most critical windows during which adverse intrauterine conditions and exposures can influence the growth and development of the fetus as well as the child's future postnatal health and behavior. Maternal cigarette smoking during pregnancy remains a relatively common but nonetheless hazardous in utero exposure. Previous studies have associated prenatal smoke exposure with reduced birth weight, poor developmental and psychological outcomes, and increased risk for diseases and behavioral disorders later in life. Researchers are now learning that many of the mechanisms whereby maternal smoke exposure may affect key pathways crucial for proper fetal growth and development are epigenetic in nature. Maternal cigarette smoking during pregnancy has been associated with altered DNA methylation and dysregulated expression of microRNA, but a deeper understanding of the epigenetics of maternal cigarette smoking during pregnancy as well as how these epigenetic changes may affect later health and behavior remain to be elucidated. This article seeks to explore many of the previously described epigenetic alterations associated with maternal cigarette smoking during pregnancy and assess how such changes may have consequences for both fetal growth and development, as well as later child health, behavior, and well-being. We also outline future directions for this new and exciting field of research.

Predictors of relapse in a bupropion trial for smoking cessation in recently-abstinent alcoholics: preliminary results using an aggregate genetic risk score.

INTRODUCTION: Rates of smoking in the US population have decreased overall, but rates in some groups, including alcoholic smokers, remain high. Many newly sober alcoholics are concerned about their smoking and some attempt to quit. However, quit rates in this population are low. Prior studies suggest risk for relapse in this population may be genetically influenced and that genetic factors may moderate response to treatment. METHODS: IN THIS EXPLORATORY STUDY, WE HAD TWO SPECIFIC AIMS: (1) to investigate associations between genetic risk and outcome; (2) to investigate whether genetic risk moderates the efficacy of a medication intervention. Data are from a subsample of 90 participants from a clinical trial of smoking cessation treatment for smokers with between 2 and 12 months of alcohol abstinence. Subjects were randomly assigned to bupropion or placebo. All subjects received counseling and nicotine patches. To examine the possibility that bupropion may have been efficacious in participants with a specific genetic profile (ie, a pharmacogenetic approach), an aggregate genetic risk score was created by combining risk genotypes previously identified in bupropion treatment studies. RESULTS: Although medication efficacy was not moderated by the aggregate genetic risk score, there was an interaction between nicotine dependence and genetic risk in predicting smoking abstinence rates at the end of treatment (10 weeks). CONCLUSIONS: Results suggest an aggregate genetic risk score approach may have utility in treatment trials of alcoholics who smoke. Additionally, these findings suggest a strategy for understanding and interpreting conflicting results for single genetic markers examined as moderators of smoking cessation treatment.

Balanced placebo design with marijuana: pharmacological and expectancy effects on impulsivity and risk taking.

RATIONALE: Marijuana is believed to increase impulsivity and risk taking, but the processes whereby it affects such behaviors are not understood. Indeed, either the pharmacologic effect of delta-9-tetrahydrocannabinol (THC) or the expectancy of receiving it may lead to deficits in cognitive processing and increases in risk taking. OBJECTIVES AND METHODS: We examined the relative effects of expecting to receive active marijuana and the pharmacological drug effects using a balanced placebo design. Young adult regular marijuana users (N = 136) were randomly assigned into one of four groups in a two × two instructional set (Told THC vs. Told no THC) by drug administration (smoked marijuana with 2.8 % THC vs. placebo) design. Dependent measures included subjective intoxication, behavioral impulsivity, and decision-making related to risky behaviors. RESULTS: Active THC, regardless of expectancy, impaired inhibition on the Stop Signal and Stroop Color-Word tasks. Expectancy of having smoked THC, regardless of active drug, decreased impulsive decision-making on a delay discounting task among participants reporting no deception and increased perception of sexual risk among women, consistent with a compensatory effect. Expectancy of smoking THC in combination with active THC increased negative perceptions from risky alcohol use. Active drug and expectancy independently increased subjective intoxication. CONCLUSIONS: Results highlight the importance of marijuana expectancy effects as users believing they are smoking marijuana may compensate for expected intoxication effects when engaged in deliberate decision-making by making less impulsive and risky decisions. Effects of marijuana on impulsive disinhibition, by contrast, reflect direct pharmacologic effects for which participants did not compensate.