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Background: Prenatal tobacco exposure (PTE) is associated with more frequent smoking among young, light smokers. Little is known about how nicotinic acetylcholine receptor (CHRN) genes may contribute to this relationship., Methods: Data were drawn from a longitudinal cohort of young light smokers of European ancestry (N = 511). Three single nucleotide polymorphisms (SNPs) among offspring, rs16969968 and rs6495308 in CHRNA5A3B4 and rs2304297 in CHRNB3A6, were analyzed with respect to whether they 1) predict PTE status; 2) confound the previously-reported effects of PTE on future smoking; 3) have effects on youth smoking frequency that are mediated through PTE; and 4) have effects that are moderated by PTE., Results: rs2304297 and rs6495308 were associated with increased likelihood and severity of PTE, respectively. In a path analysis, rs16969968 directly predicted more frequent smoking in young adulthood (B = 1.50, p = .044); this association was independent of, and not mediated by, PTE. The risk of rs16969968 (IRR = 1.07, p = .015) and the protective effect of rs2304297 (IRR = 0.84, p < .001) on smoking frequency were not moderated by PTE. PTE moderated the effect of rs6495308, such that these alleles were protective against later smoking frequency only among non-exposed youth (IRR = 0.85, p < .001)., Conclusions: The association between offspring CHRNB3A6 and PTE is a novel finding. The risk of rs16969968 on youth smoking is independent and unrelated to that of PTE among young, light smokers. PTE moderates the protective effect of rs6495308 on youth smoking frequency. However, PTE's pathway to youth smoking behavior was not explained by these genetic factors, leaving its mechanism(s) of action unclear., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: Prior research suggests the CHRNA5A3B4 and CHRNB3A6 gene clusters have independent effects on smoking progression in young smokers. Here classification tree analysis uncovers conditional relations between these genes., Methods: Conditional classification tree and random forest analyses were employed to predict daily smoking at 6-year follow-up in a longitudinal sample of young smokers (N = 480) who had smoked at least one puff at baseline and were of European ancestry. Potential predictors included gender, lifetime smoking, Nicotine Dependence Syndrome Scale (NDSS), and five single nucleotide polymorphisms (SNPs) tagging CHRNB3A6 and CHRNA5A3B4 Haplotypes A, B, and C. Conditional random forest analysis was used to calculate variable importance., Results: The classification tree identified NDSS, the CHRNB3A6 SNP rs2304297, and the CHRNA5A3B4 Haplotype C SNP rs6495308 as predictive of year 6 daily smoking with the baseline NDSS identified as the strongest predictor. The CHRNB3A6 protective effect was contingent on a lower level of baseline NDSS, whereas the CHRNA5A3B4 Haplotype C protective effect was seen at a higher level of baseline NDSS. A CHRNA5A3B4 Haplotype C protective effect also was observed in participants with low baseline NDSS who had no CHRNB3A6 rs2304297 minor allele., Conclusions: The protective effects of CHRNA5A3B4 Haplotype C and CHRNB3A6 on smoking progression are conditional on different levels of baseline cigarette use. Also, duplicate dominant epistasis between SNPs indicated the minor allele of either SNP afforded comparable protective effects in the absence of a minor allele at the other locus. Possible mechanisms underlying these conditional relations are discussed., Implications: The substantive contributions of this paper are the demonstration of a difference in the protective effects of CHRNB3A6 and CHRNA5A3B4 Haplotype C in young smokers attributable to level of cigarette use, as well as observation of duplicate dominant epistasis between the two markers. The methodological contribution is demonstrating that classification tree and random forest statistical methods can uncover conditional relations among genetic effects not detected with more common regression methods., (© The Author 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: In very novice smokers, CYP2A6 genotypes that reduce nicotine metabolism to an intermediate rate may increase smoking risk, relative to both normal and slow rates. The present study examined the hypothesis that intermediate metabolism variants are associated with greater pleasurable effects of the initial smoking attempt than either normal or slow metabolism variants., Methods: Participants were novice smokers (N = 261, 65% female) of European descent. Predicted nicotine metabolic rate based on CYP2A6 diplotypes (CYP2A6 Diplotype Predicted Rate [CDPR]) was partitioned into Normal, Intermediate, and Slow categories using a metabolism metric. Subjective reactions to the initial smoking attempt were assessed by the Pleasurable Smoking Experiences (PSE) scale, which was collected within 3 years of the initial smoking attempt. The effect of CDPR on PSE was tested using a generalized linear model in which CDPR was dummy coded and Intermediate CDPR was the reference condition. Gender was included in the model as a control for higher PSE scores by males., Results: Lower PSE scores were associated with Normal CDPR, β = -0.34, P = .008, and Slow CDPR, β = -0.52, P = .001, relative to Intermediate CDPR., Conclusions: Intermediate CDPR-enhanced pleasurable effects of the initial smoking attempt relative to other CYP2A6 variants. This finding is consistent with the hypothesis that the risk effect of Intermediate CDPR on early smoking is a function of optimal pleasurable effects., Implications: This study supports our recent hypothesis that CYP2A6 diplotypes that encode intermediate nicotine metabolism rate are associated with enhanced pleasurable events following the initial smoking attempt, compared with diplotypes that encode either normal or slow metabolism. This hypothesis was offered to account for our unexpected previous finding of enhanced smoking risk in very novice smokers associated with intermediate metabolism rate. Our new finding encourages further investigation of time-dependent relations between CYP2A6 effects and smoking motives, and it encourages laboratory study of the mechanisms underlying the initial smoking enhancement in novice smokers associated with intermediate metabolism., (© The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The mu1 opioid receptor gene, OPRM1, has long been a high-priority candidate for human genetic studies of addiction. Because of its potential functional significance, the non-synonymous variant rs1799971 (A118G, Asn40Asp) in OPRM1 has been extensively studied, yet its role in addiction has remained unclear, with conflicting association findings. To resolve the question of what effect, if any, rs1799971 has on substance dependence risk, we conducted collaborative meta-analyses of 25 datasets with over 28,000 European-ancestry subjects. We investigated non-specific risk for "general" substance dependence, comparing cases dependent on any substance to controls who were non-dependent on all assessed substances. We also examined five specific substance dependence diagnoses: DSM-IV alcohol, opioid, cannabis, and cocaine dependence, and nicotine dependence defined by the proxy of heavy/light smoking (cigarettes-per-day >20 vs. ≤ 10). The G allele showed a modest protective effect on general substance dependence (OR = 0.90, 95% C.I. [0.83-0.97], p value = 0.0095, N = 16,908). We observed similar effects for each individual substance, although these were not statistically significant, likely because of reduced sample sizes. We conclude that rs1799971 contributes to mechanisms of addiction liability that are shared across different addictive substances. This project highlights the benefits of examining addictive behaviors collectively and the power of collaborative data sharing and meta-analyses.

Introduction: The present study sought to identify time-dependent within-participant effects of CYP2A6 genotypes on smoking frequency and nicotine dependence in young smokers., Methods: Predicted nicotine metabolic rate based on CYP2A6 diplotypes (CYP2A6 diplotype predicted rate [CDPR]) was partitioned into Normal, Intermediate, and Slow categories using a metabolism metric. Growth-curve models characterized baseline and longitudinal CDPR effects with data from eight longitudinal assessments during a 6-year period (from approximately age 16-22) in young smokers of European descent (N = 296, 57% female) who had smoked less than 100 cigarettes lifetime at baseline and more than that amount by Year 6. Phenotypes were number of days smoked during the previous 30 days and a youth version of the Nicotine Dependence Syndrome Scale (NDSS). A zero-inflated Poisson growth-curve model was used to account for the preponderance of zero days smoked., Results: At baseline, Intermediate CDPR was a risk factor relative to both Normal and Slow CDPR for smoking frequency and the NDSS. Slow CDPR was associated with the highest probability of smoking discontinuation at baseline. However, due to CDPR time trend differences, by young adulthood these baseline effects had been reordered such that the greatest risks for smoking frequency and the NDSS were associated with Normal CDPR., Conclusions: Reduced metabolism CYP2A6 genotypes are associated with both risk and protective effects in novice smokers. However, differences in the time-by-CDPR effects result in a reordering of genotype effects such that normal metabolism becomes the risk variant by young adulthood, as has been reliably reported in older smokers., (© The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Binge drinking is responsible for over half of all alcohol-related deaths and results in significant health and economic costs to individuals and society. Knowledge of genetic aspects of this behavior, particularly as it emerges in young adulthood, could lead to improved treatment and prevention programs., Methods: We have focused on the association of variation in neuronal nicotinic receptor subunit genes (CHRNs) in a cohort of 702 Hispanic and non-Hispanic White young adults who are part of the Social and Emotional Contexts of Adolescent Smoking Patterns (SECASP) study. Fifty-five single nucleotide polymorphisms (SNPs) covering the variation in 5 CHRNs (CHRNA4, CHRNB2, CHRNA2, CHRNB3A6, and CHRNA5A3B4) were studied., Results: Frequency of binge drinking and other correlated alcohol consumption measures were significantly associated with SNPs in CHRNA4 (p-values ranged from 0.0003 to 0.02), but not with SNPs in other CHRNs. This association was independent of smoking status in our cohort., Conclusions: Variants in CHRNA4 may contribute to risk of binge drinking in young adults in this cohort. Results will need to be confirmed in independent samples., (Copyright © 2014 by the Research Society on Alcoholism.)

Introduction: Few studies have sought to identify specific genetic markers associated with cigarettes per day (CPD) during adolescence and young adulthood, the period of greatest vulnerability for the development of nicotine dependence., Methods: We used a longitudinal design to investigate the effect of neuronal nicotinic acetylcholine receptor (CHRN) subunit genes on CPD from 15 to 21 years of age in young smokers of European descent (N = 439, 59% female). The number of CPD typically smoked during the previous 30 days was self-reported. Single nucleotide polymorphisms (SNPs) from CHRN genes were genotyped using DNA extracted from saliva samples collected at the 5-year assessment. Mixed-model analyses of SNP effects were computed across age at the time of assessment using log-transformed CPD as the phenotype. Data from the 1000 Genomes Project were used to clarify the architecture of CHRN genes to inform SNP selection and interpretation of results., Results: CPD was associated with a CHRNB3A6 region tagged by rs2304297, with CHRNA5A3B4 haplotype C (tagged by rs569207), and with the CHRNA2 SNP rs2271920, ps < .004. The reliability of single-SNP associations was supported by the correspondence between a more extensive set of SNP signals and the underlying genetic architecture. The 3 signals identified in this study appear to make independent contributions to CPD, and their combined effect accounts for 5.5% of the variance in log-transformed CPD., Conclusions: Level of CPD during adolescence and young adulthood is associated with CHRNB3A6, CHRNA5A3B4, and CHRNA2.

Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype., (© 2013 WILEY PERIODICALS, INC.)

Context: Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968., Objective: To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking., Data Sources: Primary data., Study Selection: Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy., Data Extraction: Uniform statistical analysis scripts were run locally. Starting with 94,050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD >20) and light smokers (CPD ≤10) with age-at-onset information, reducing the sample size to 33,348. Each study was stratified into early-onset smokers (age at onset ≤16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavy vs light smoking with the rs16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum., Data Synthesis: Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR] = 1.45; 95% CI, 1.36-1.55; n = 13,843) than were carriers of the risk allele who were late-onset smokers (OR = 1.27; 95% CI, 1.21-1.33, n = 19,505) (P = .01)., Conclusion: These results highlight an increased genetic vulnerability to smoking in early-onset smokers.

Objective: Smoking is highly intractable, and the genetic influences on cessation are unclear. Identifying the genetic factors affecting smoking cessation could elucidate the nature of tobacco dependence, enhance risk assessment, and support development of treatment algorithms. This study tested whether variants in the nicotinic receptor gene cluster CHRNA5-CHRNA3-CHRNB4 predict age at smoking cessation and relapse after an attempt to quit smoking., Method: In a community-based, crosssectional study (N=5,216) and a randomized comparative effectiveness smoking cessation trial (N=1,073), the authors used Cox proportional hazard models and logistic regression to model the relationships of smoking cessation (self-reported quit age in the community study and point-prevalence abstinence at the end of treatment in the clinical trial) to three common haplotypes in the CHRNA5-CHRNA3-CHRNB4 region defined by rs16969968 and rs680244., Results: The genetic variants in the CHRNA5-CHRNA3-CHRNB4 region that predict nicotine dependence also predicted a later age at smoking cessation in the community sample. In the smoking cessation trial, haplotype predicted abstinence at end of treatment in individuals receiving placebo but not among individuals receiving active medication. Haplotype interacted with treatment in affecting cessation success., Conclusions: Smokers with the high-risk haplotype were three times as likely to respond to pharmacologic cessation treatments as were smokers with the low-risk haplotype. The high-risk haplotype increased the risk of cessation failure, and this increased risk was ameliorated by cessation pharmacotherapy. By identifying a high-risk genetic group with heightened response to smoking cessation pharmacotherapy, this work may support the development of personalized cessation treatments.

Recently, genetic association findings for nicotine dependence, smoking behavior, and smoking-related diseases converged to implicate the chromosome 15q25.1 region, which includes the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit genes. In particular, association with the nonsynonymous CHRNA5 SNP rs16969968 and correlates has been replicated in several independent studies. Extensive genotyping of this region has suggested additional statistically distinct signals for nicotine dependence, tagged by rs578776 and rs588765. One goal of the Consortium for the Genetic Analysis of Smoking Phenotypes (CGASP) is to elucidate the associations among these markers and dichotomous smoking quantity (heavy versus light smoking), lung cancer, and chronic obstructive pulmonary disease (COPD). We performed a meta-analysis across 34 datasets of European-ancestry subjects, including 38,617 smokers who were assessed for cigarettes-per-day, 7,700 lung cancer cases and 5,914 lung-cancer-free controls (all smokers), and 2,614 COPD cases and 3,568 COPD-free controls (all smokers). We demonstrate statistically independent associations of rs16969968 and rs588765 with smoking (mutually adjusted p-values<10(-35) and <10(-8) respectively). Because the risk alleles at these loci are negatively correlated, their association with smoking is stronger in the joint model than when each SNP is analyzed alone. Rs578776 also demonstrates association with smoking after adjustment for rs16969968 (p<10(-6)). In models adjusting for cigarettes-per-day, we confirm the association between rs16969968 and lung cancer (p<10(-20)) and observe a nominally significant association with COPD (p = 0.01); the other loci are not significantly associated with either lung cancer or COPD after adjusting for rs16969968. This study provides strong evidence that multiple statistically distinct loci in this region affect smoking behavior. This study is also the first report of association between rs588765 (and correlates) and smoking that achieves genome-wide significance; these SNPs have previously been associated with mRNA levels of CHRNA5 in brain and lung tissue., Competing Interests: NLS is the spouse of S.F. Saccone, who is listed as an inventor on a patent, “Markers of Addiction”, covering the use of certain SNPs in diagnosing, prognosing, and treating addiction. LJB, JCW and JPR are listed as inventors on a patent, “Markers of Addiction,” covering the use of certain SNPs in diagnosing, prognosing, and treating addiction. LJB has served as a consultant to Pfizer in 2008. XK is a full time employee of GlaxoSmithKline. SP was a full time employee of GlaxoSmithKline. Current affiliation is with Hoffman-La Roche. JK has served as a consultant to Pfizer in 2008. MDL has served as a consultant to NIH, deCODE genetics, University of Pennsylvania, Reckitt Benckiser Pharmaceuticals, Pennsylvania Department of Health, and Informational Managements Consulting. Dr. Li also serves as a scientific advisor to ADial Pharmaceuticals. TJP receives compensation from the University of Mississippi Medical Center; part of his salary has been supported by grants from NIDA, NCI, the University of Mississippi Health Care Cancer Institute, the Mississippi State Department of Health, Pfizer Inc., and GlaxoSmithKline.

Background: Autism Spectrum Disorders (ASD) are phenotypically heterogeneous, characterized by impairments in the development of communication and social behaviour and the presence of repetitive behaviour and restricted interests. Dissecting the genetic complexity of ASD may require phenotypic data reflecting more detail than is offered by a categorical clinical diagnosis. Such data are available from the Social Responsiveness Scale (SRS) which is a continuous, quantitative measure of social ability giving scores that range from significant impairment to above average ability., Methods: We present genome-wide results for 64 multiplex and extended families ranging from two to nine generations. SRS scores were available from 518 genotyped pedigree subjects, including affected and unaffected relatives. Genotypes from the Illumina 6 k single nucleotide polymorphism panel were provided by the Center for Inherited Disease Research. Quantitative and qualitative analyses were done using MCLINK, a software package that uses Markov chain Monte Carlo (MCMC) methods to perform multilocus linkage analysis on large extended pedigrees., Results: When analysed as a qualitative trait, linkage occurred in the same locations as in our previous affected-only genome scan of these families, with findings on chromosomes 7q31.1-q32.3 [heterogeneity logarithm of the odds (HLOD) = 2.91], 15q13.3 (HLOD = 3.64), and 13q12.3 (HLOD = 2.23). Additional positive qualitative results were seen on chromosomes 6 and 10 in regions that may be of interest for other neuropsychiatric disorders. When analysed as a quantitative trait, results replicated a peak found in an independent sample using quantitative SRS scores on chromosome 11p15.1-p15.4 (HLOD = 2.77). Additional positive quantitative results were seen on chromosomes 7, 9, and 19., Conclusions: The SRS linkage peaks reported here substantially overlap with peaks found in our previous affected-only genome scan of clinical diagnosis. In addition, we replicated a previous SRS peak in an independent sample. These results suggest the SRS is a robust and useful phenotype measure for genetic linkage studies of ASD. Finally, analyses of SRS scores revealed linkage peaks overlapping with evidence from other studies of neuropsychiatric diseases. The information available from the SRS itself may, therefore, reveal locations for autism susceptibility genes that would not otherwise be detected.

Background: It has been suggested that efforts to identify genetic risk markers of autism spectrum disorder (ASD) would benefit from the analysis of more narrowly defined ASD phenotypes. Previous research indicates that 'insistence on sameness' (IS) and 'repetitive sensory-motor actions' (RSMA) are two factors within the ASD 'repetitive and stereotyped behavior' domain. The primary aim of this study was to identify genetic risk markers of both factors to allow comparison of those markers with one another and with markers found in the same set of pedigrees using ASD diagnosis as the phenotype. Thus, we empirically addresses the possibilities that more narrowly defined phenotypes improve linkage analysis signals and that different narrowly defined phenotypes are associated with different loci. Secondary aims were to examine the correlates of IS and RSMA and to assess the heritability of both scales., Methods: A genome-wide linkage analysis was conducted with a sample of 70 multiplex ASD pedigrees using IS and RSMA as phenotypes. Genotyping services were provided by the Center for Inherited Disease Research using the 6 K single nucleotide polymorphism linkage panel. Analysis was done using the multipoint linkage software program MCLINK, a Markov chain Monte Carlo (MCMC) method that allows for multilocus linkage analysis on large extended pedigrees., Results: Genome-wide significance was observed for IS at 2q37.1-q37.3 (dominant model heterogeneity lod score (hlod) 3.42) and for RSMA at 15q13.1-q14 (recessive model hlod 3.93). We found some linkage signals that overlapped and others that were not observed in our previous linkage analysis of the ASD phenotype in the same pedigrees, and regions varied in the range of phenotypes with which they were linked. A new finding with respect to IS was that it is positively associated with IQ if the IS-RSMA correlation is statistically controlled., Conclusions: The finding that IS and RSMA are linked to different regions that only partially overlap regions previously identified with ASD as the phenotype supports the value of including multiple, narrowly defined phenotypes in ASD genetic research. Further, we replicated previous reports indicating that RSMA is more strongly associated than IS with measures of ASD severity.

Introduction: Previous research revealed significant associations between haplotypes in the CHRNA5-A3-B4 subunit cluster and scores on the Fagerström Test for Nicotine Dependence among individuals reporting daily smoking by age 17. The present study used subsamples of participants from that study to investigate associations between the CHRNA5-A3-B4 haplotypes and an array of phenotypes not analyzed previously (i.e., withdrawal severity, ability to stop smoking, and specific scales on the Wisconsin Inventory of Smoking Dependence Motives (WISDM-68) that reflect loss of control, strong craving, and heavy smoking., Methods: Two cohorts of current or former smokers (N = 886) provided both self-report data and DNA samples. One sample (Wisconsin) comprised smokers making a quit smoking attempt, which permitted the assessment of withdrawal and relapse during the attempt. The other sample (Utah) comprised participants studied for risk factors for nicotine dependence and chronic obstructive pulmonary disease and included individuals originally recruited in the Lung Health Study., Results: The CHRNA5-A3-B4 haplotypes were significantly associated with the targeted WISDM-68 scales (Tolerance, Craving, Loss of Control) in both samples of participants but only among individuals who began smoking early in life. The haplotypes were significantly associated with relapse likelihood and withdrawal severity, but these associations showed no evidence of an interaction with age at daily smoking., Discussion: The CHRNA5-A3-B4 haplotypes are associated with a broad range of nicotine dependence phenotypes, but these associations are not consistently moderated by age at initial smoking.

The construct of tobacco dependence is important from both scientific and public health perspectives, but it is poorly understood. The current research integrates person-centered analyses (e.g., latent profile analysis) and variable-centered analyses (e.g., exploratory factor analysis) to clarify the latent structure of nicotine dependence and to guide distillation of the phenotype. Using data from 4 samples of smokers, latent profiles were derived using the Wisconsin Inventory of Smoking Dependence Motives subscale scores. Across all 4 samples, results revealed a unique latent profile that had relative elevations on 4 subscales (Automaticity, Craving, Loss of Control, and Tolerance). Variable-centered analyses supported the uniqueness of these 4 subscales as they constituted a distinct common factor and were the strongest predictors of relapse and other dependence criteria. Conversely, the remaining 9 motives carried little unique predictive validity regarding dependence. Applications of a factor mixture model further supported the presence of a unique class of smokers in relation to a common factor underlying the 4 subscales. The results suggest that a pattern of smoking that is heavy, pervasive, automatic, and relatively unresponsive to instrumental contingencies is a necessary and sufficient condition for severe nicotine dependence., ((PsycINFO Database Record (c) 2008 APA, all rights reserved).)

People who begin daily smoking at an early age are at greater risk of long-term nicotine addiction. We tested the hypothesis that associations between nicotinic acetylcholine receptor (nAChR) genetic variants and nicotine dependence assessed in adulthood will be stronger among smokers who began daily nicotine exposure during adolescence. We compared nicotine addiction-measured by the Fagerstrom Test of Nicotine Dependence-in three cohorts of long-term smokers recruited in Utah, Wisconsin, and by the NHLBI Lung Health Study, using a candidate-gene approach with the neuronal nAChR subunit genes. This SNP panel included common coding variants and haplotypes detected in eight alpha and three beta nAChR subunit genes found in European American populations. In the 2,827 long-term smokers examined, common susceptibility and protective haplotypes at the CHRNA5-A3-B4 locus were associated with nicotine dependence severity (p = 2.0x10(-5); odds ratio = 1.82; 95% confidence interval 1.39-2.39) in subjects who began daily smoking at or before the age of 16, an exposure period that results in a more severe form of adult nicotine dependence. A substantial shift in susceptibility versus protective diplotype frequency (AA versus BC = 17%, AA versus CC = 27%) was observed in the group that began smoking by age 16. This genetic effect was not observed in subjects who began daily nicotine use after the age of 16. These results establish a strong mechanistic link among early nicotine exposure, common CHRNA5-A3-B4 haplotypes, and adult nicotine addiction in three independent populations of European origins. The identification of an age-dependent susceptibility haplotype reinforces the importance of preventing early exposure to tobacco through public health policies., Competing Interests: The authors have declared that no competing interests exist.

The Patient Health Questionnaire-9 (PHQ-9; R. L. Spitzer, K. Kroenke, J. B. W. Williams, & The Patient Health Questionnaire Primary Care Study Group, 1999), modified to ask about the worst period of depression lifetime, was validated against lifetime mood disorder diagnoses established by the Structured Clinical Interview for DSM-IV (SCID; M. B. First, R. L. Spitzer, M. Gibbon, & J. B. W. Williams, 2001) in 526 participants. PHQ-9 dichotomous scores corresponded highly with major depressive episode (MDE) Criterion A, MDE, and major depressive disorder (MDD), odds ratios >or= 9.5, and area under the receiver operating characteristic curve (AUC) >or= 0.84. The continuous scale score was higher in participants who did (M=17.14, SD=7.36) than in those who did not (M=6.05, SD=6.29) meet MDE Criterion A, t(524)=18.09, p<.001; was correlated with number of MDE Criterion A symptoms, r(525)=.67, p<.001; and detected MDE Criterion A (AUC=0.88). The PHQ-9 as a lifetime measure may be used to complement or replace more costly interview assessments., ((c) 2007 APA, all rights reserved)

Phenotypic evidence indicates that the ability to taste the bitter compounds phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP) may protect against cigarette smoking. In this study, PTC gene haplotypes were found to be associated with both the odds of being a smoker and the importance of cigarette taste as a smoking motive. Smokers (n = 384) and nonsmokers (n = 183) were genotyped for polymorphisms that affect taste sensitivity to PTC and PROP. The "taster" PAV haplotype, relative to the "nontaster" AVI haplotype, was predicted to be associated with reduced odds of being a smoker and lower taste motivation as measured by the Wisconsin Inventory of Smoking Dependence Motives-68 taste/sensory processes scale. The results did not support the predicted association between the PAV and AVI haplotypes and smoker odds, but the AAV haplotype, which confers intermediate PTC/PROP taste sensitivity, was associated with reduced smoker prevalence (49% vs. 70%), chi(2)(1, N = 567) = 10.392, p = .001. The predicted relationship between PAV and AVI and taste motivation was found, F(2, 348) = 3.303, p = .038. The results encourage further exploration of the role of taste/sensory processes in tobacco dependence.

Objective: To evaluate the relative effectiveness of computer and manual reminder systems on the implementation of a clinical practice guideline., Design: Seventy-eight outpatients in a mental health clinic were randomly assigned within clinician to one of the two reminder systems. The computer system, called CaseWalker, reminded clinicians when guideline-recommended screening for mood disorder was due, ensured the fidelity of the diagnosis of major depressive disorder to criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), and generated a progress note. The manual system was a checklist inserted in the paper medical record., Measures: Screening rates for mood disorder and the completeness of the documentation of which DSM-IV criteria were met by patients who were said to have major depressive disorder were compared., Results: The CaseWalker, compared with the paper checklist, resulted in a higher screening rate for mood disorder (86.5 vs. 61 percent, P = 0.008) and a higher rate of complete documentation of DSM-IV criteria (100 vs. 5.6 percent, P < 0.001)., Conclusions: In an outpatient mental health clinic, computer reminders were shown to be superior to manual reminders in improving adherence to a clinical practice guideline for depression.

Male alcoholics (N = 85) were followed for 6 months after inpatient treatment for alcohol dependence. Latency to relapse was predicted by two related persistence measures (the RD2 Persistence scale and the Orderliness/Persistence factor scale of the Tridimensional Personality Questionnaire, TPQ) as well as by job status at the time of admission to treatment, a history of vagrancy or public intoxication, amount of prior substance abuse treatment and the number of criteria met for a diagnosis of Antisocial Personality Disorder. Persistence predicted relapse latency even when the other predictors were used as covariates, supporting the hypothesis that normal-range personality variables may enhance the prediction of clinical outcome. Further, the relations between TPQ scales and antisocial behavior as well as the severity of alcohol dependence were examined.

Initial self-administration of high doses of EtOH is shown to be associated in some inbred rat strains with the eventual development of a low preference for EtOH, presumably as a consequence of taste aversion learning occurring during initial intake. Only modest support was obtained for the hypothesis that strain differences in the aversiveness of EtOH affects taste aversion learning. The instrinsic palatability of EtOH and the salience of EtOH as a conditioned stimulus may also affect EtOH preference, but there do not appear to be differences among strains in their general ability to form taste-toxicosis associations.

The affective correlates of alcohol and cocaine use were investigated in two studies. In the first, alcoholics (n = 50) and cocaine addicts (n = 40) were administered factor scales from the Inventory of Drinking Situations as well as the General Temperament Survey. Substance use in negative affect states was reported more often by alcoholics than by cocaine addicts, even when age and race differences were statistically controlled. Alcoholics also reported higher levels of negative temperament, and substance use in negative affect states was correlated with negative temperament across groups. In a study using subjects dependent on both drugs (n = 21), alcohol was more likely to be used in negative affect situations than was cocaine. Thus, the affective correlates of substance use are associated with both individual differences and drug-specific effects. Possible reasons for the differential association of alcohol with negative affect are proposed.

In 2 experiments we investigated the effects of withdrawal and stress on the affective correlates of urges to smoke. In both, habitual cigarette smokers were divided into continuing and withdrawing smoker groups. In the 1st study, 44 adults reported current mood, urge, and expectations over a 24-hr period. In the 2nd, a controlled laboratory study, urge, affect, and physiological data were obtained from continuing and withdrawing groups (N = 64) exposed to high- or low-stress conditions. Urges among withdrawing smokers were positively associated with negative affect and negatively associated with positive affect; continuing smokers reported urges that were directly associated with positive affect and unrelated to negative affect. Stress and withdrawal produced urge self-reports that were related to negative affect. Moreover, subjects who smoked after exposure to withdrawal and stress reported greater pleasure and arousal than did other subjects.

Saccharin aversions were conditioned using ethanol (EtOH) in rats of different body weights. There was a nonuniform relation between EtOH dose (g/kg) and strength of conditioned taste aversion. Heavier rats learned stronger aversions at the same dose, and a weak dose (i.e., 1.0 g/kg) was effective only in heavier rats. It is suggested that rats be equated on body weight in studies of EtOH-induced taste aversion learning and in studies of EtOH preference.

Male alcoholics (n = 336) were given the Inventory of Drinking Situations (IDS), a 100-item questionnaire that asks subjects to rate the frequency with which they drank in various situations during the previous year. A principal components analysis of the responses suggests there are three major categories of situations in which alcoholics are likely to drink: negative affect states, positive affect states combined with social cues to drink, and attempts to test one's ability to control one's drinking. These categories are compared with recent empirical attempts to define categories of alcohol and smoking relapse.

The development of taste aversions was studied in 34 oncology patients undergoing radiotherapy. A target flavor was paired with irradiation on four consecutive treatment days. Self-reported nausea on treatment days reliably predicted aversion learning. The implications of this finding for the anorexia of cancer patients and the role of nausea in human taste aversion learning are discussed.

Taste-mediated learning is relevant to the alcohol consumption patterns of animals. This review concludes that taste aversion learning has thus far prevented development of an animal model of alcoholism. The presence of a taste cue, lack of control over alcohol administration, and high alcohol concentrations or dosages all facilitate the development of alcohol aversions. There is little evidence that taste preference learning is involved in the development of alcohol dependence. Data from taste-mediated learning research with animals are consistent with drinking patterns of human alcoholics.

Eight halfway houses for alcoholics were surveyed and compared to other halfway houses for alcoholics, and halfway houses for the non-alcoholic mentally ill, as described in previous studies. The halfway houses for alcoholics surveyed in the present report may be separated into two principal groups: (a) a self-supporting profit-oriented type with an autonomous owner-operator, and (b) a board-controlled and supported type usually receiving group or institutional support. Regardless of group membership, however, none of the halfway houses for alcoholics in the present study matched the high standards set by halfway houses for the non-alcoholic mentally ill as described in other reports. Recent events indicate that halfway houses will be responsible for an increasing portion of persons requiring a structured, supportive or sheltered environment. This paper examines the ability of halfway houses for alcoholics to provide adequate residential care services. Additionally, disparities between alcoholism and non-alcoholism halfway houses regarding staffing, professionalised orientation, and adjunct services are scrutinised. The effectiveness of halfway houses is analysed, and suggestions for future utilisation of alcoholic halfway houses are advanced.

Patients who volunteered for a controlled drinking training program had more severe alcohol problems and less social and family stability than those who opted for abstinence-oriented programs.

Zinc (Zn) deficiency is shown to condition aversion to the Zn-deficient diet. After development of a Zn deficiency syndrome during which consumption of the deficient diet decreased, rats readily consumed a familiar Zn-normal diet. After Zn repletion, the previously deficient animals continued to avoid the Zn-deficient diet. These results would not be predicted by the competing hypothesis that Zn-deficiency is anorexigenic.

A study was undertaken to assess the effectiveness of treating alcoholics after detoxification for the very commonly observed syndrome of anxiety, depression, and somatic complaints. Previous studies had indicated that these patients generally respond quite well to drug treatment with the phenothiazine class of drugs. However, a double blind placebo-controlled study of adequate size had not been undertaken. Forty-five comparably addicted male alcoholics with anxiety or mixed anxiety-depression from an inpatient alcohol treatment ward comprised the treatment group. Twenty-three patients received thioridazine treatment and 22 received placebo treatment in a double blind fashion after acute withdrawal from alcohol. Progress over a 4-week period was measured with standard rating instruments--the Hamilton Rating Scale for Depression (by physician) and the Zung and Lipman Self-Rating Scales. Both placebo and active medication groups improved symptomatically during the 4-week program. The thioridazine group had significantly better improvement in sleep disturbance (early, middle, and late insomnia) than the placebo group. There was also significantly better improvement in anxiety with thioridazine as compared with placebo. Interestingly, the placebo group had significantly better work and activity (as appraised by the ward physician) than the thioridazine group. The authors note that active drug effect might actually hamper some patients in their rehabilitative effort, especially if phenothiazines of the more sedating variety are used. Since alcohol rehabilitation generally utilizes a wide range of activities (such as didactic sessions, occupation therapy, group therapy), alertness and performance ability appear to be important factors in the rehabilitation program. Although thioridazine treatment for some patients with anxiety and insomnia would appear to be quite helpful, its blanket use for the post-detoxification anxiety-depression of the alcoholic might be detrimental for others and cannot be recommended as a routine treatment strategy in an alcohol rehabilitation program.

Fifteen acute myocardial infarction patients (only one of whom had evidence of significant renal dysfunction) received a constant-rate intravenous infusion of procainamide at one rate for a least 24 hours. Steady-state plasma levels achieved during these infusions were used to calculate total body clearance (C/B). Linear regression analysis of C/B versus a variety of clinical and laboratory patient characteristics yielded only body weight (or parameters derived from it) as a significant covariant (r = 0.713, P less than or equal to 0.005). Interestingly, the data from these 15 patients suggest that the presence of a significant degree of heart failure at the start of therapy did not result in a significant decrease in C/B (C/B = 5.9 ml/min/kg when class 0-I failure was present at the start of therapy and C/B = 5.5 ml/min/kg when class III-IV failure was present). If the data from five other patients who were studied previously are added to the group reported here, the conclusions reached would be the same. These data suggest that in patients with good renal and hepatic function, initial procainamide infusion rate could be selected on the basis of body weight and need not consider the initial presence of moderate heart failure. However, intense clinical monitoring for signs of impeding serious toxicity is strongly recommended since the observed regression line did not predict total body clearance accurately in 10-15 per cent of the patients studied.

Six experiments with rats investigated the conditions under which one flavor interferes with aversion conditioning to a second, familiar flavor. Conditioning to the familiar flavor was weakest when the interference flavor was contiguous to lithium-induced toxicosis, novel, more intense, and strongly associated with toxicosis. In addition, conditioning to the familiar flavor was weakened even if multiple conditioning trials were used. The repeated finding of an inverse relationship between strength of aversion to the target and interference flavors is interpreted as support for an associative competition hypothesis of the interference effect. The possible relevance of the interference effect to the attenuation of taste aversions in cancer patients is discussed.

Correspondence of the Minnesota Multiphasic Personality Inventory (MMPI) posttraumatic stress disorder (PTSD) subscale and the clinical scale decision rules reported by Keane, Malloy, and Fairbank (1984) with clinical diagnoses of PTSD was measured on a sample of 595 veterans. The measures demonstrated good sensitivity and selectivity, but the false-positive rate was high. It is suggested the MMPI measures be used to rule out, but not to establish, the diagnosis of PTSD. The construct validity of the PTSD subscale was supported by the finding of a higher mean score in combat than noncombat veterans.

Taste aversion learning was investigated in two inbred strains of rats known to differ in amount of ethanol (EtOH) they will self-administer orally. The "low EtOH preference" strain, WKYs, acquired an aversion to an EtOH solution during self-administration; but a "high preference" strain, M520s, did not. It was shown that a lower dose of EtOH will condition saccharin aversion in WKYs than in M520s, suggesting EtOH is a more effective US in the low preference strain. Analysis of patterns of EtOH self-administration indicates the pattern of the low preference strain is more likely to result in taste aversion learning. The implications of these results for the presumed relation between EtOH preference and other EtOH-related phenotypes is discussed.

Disruption of taste aversion learning following the administration of the same drug prior to and during conditioning (intra-agent disruption) was shown to be greater than disruption following the administration of one drug prior to conditioning and another during conditioning (inter-agent disruption). Comparable dosages of ethanol and lithium chloride served as unconditioned stimuli. Inter-agent disruptions are attributed to a dissociation of conditioned and unconditioned stimuli, while intra-agent disruptions are attributed to both a dissociative effect and drug-specific effects. Intra-agent disruption was correlated with an independent measure of tolerance, suggesting tolerance constitutes at least a portion of the drug-specific effects.

Ethanol (EtOH) oral self-administration studies using rats have had inconsistent outcomes: studies in which rats are fluid deprived report decreasing EtOH intake over trials, whereas studies not employing fluid deprivation report increasing intake over trials. The present study supports the hypothesis that differential taste aversion learning may account for some of this discrepancy. This study indicates that taste aversion learning is maximized under fluid deprivation conditions and that "latent inhibition," i.e., exposure to non-intoxicating amounts of the EtOH solution prior to conditioning, reduces taste aversion learning. It is suggested that the effect of fluid deprivation on taste aversion resulting from EtOH self-administration may be at least in part due to the development of latent inhibition in non-deprived animals during initial exposure to the EtOH solution.

One taste-aversion study using male Long-Evans rats in which ethanol was the unconditioned stimulus (UCS) and six studies in which lithium chloride (LiCl) was the UCS demonstrate that (a) exposure to the UCS prior to conditioning retards subsequent acquisition of learned taste aversions; (b) a single preconditioning UCS exposure is sufficient to attenuate conditioning; (c) the preconditioning UCS exposure must occur within a limited period prior to conditioning to attenuate learning; (d) repeated conditioning trials will override the effect of prior exposure to the UCS; (e) tolerance to the UCS is not a necessary condition for the attenuation effect to occur; (f) pairing the preconditioning UCS with a novel flavor other than the CS does not remove the preexposure effect, although it may reduce its magnitude; and (g) the degree of disruption is a positive function of preconditioning UCS dosage and an inverse function of conditioning UCS dosage.