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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

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.

Suicide is the 10th leading cause of death in the United States. Although environment has undeniable impact, evidence suggests that genetic factors play a significant role in completed suicide. We linked a resource of ~ 4500 DNA samples from completed suicides obtained from the Utah Medical Examiner to genealogical records and medical records data available on over eight million individuals. This linking has resulted in the identification of high-risk extended families (7–9 generations) with significant familial risk of completed suicide. Familial aggregation across distant relatives minimizes effects of shared environment, provides more genetically homogeneous risk groups, and magnifies genetic risks through familial repetition. We analyzed Illumina PsychArray genotypes from suicide cases in 43 high-risk families, identifying 30 distinct shared genomic segments with genome-wide evidence (p = 2.02E-07–1.30E-18) of segregation with completed suicide. The 207 genes implicated by the shared regions provide a focused set of genes for further study; 18 have been previously associated with suicide risk. Although PsychArray variants do not represent exhaustive variation within the 207 genes, we investigated these for specific segregation within the high-risk families, and for association of variants with predicted functional impact in ~ 1300 additional Utah suicides unrelated to the discovery families. None of the limited PsychArray variants explained the high-risk family segregation; sequencing of these regions will be needed to discover segregating risk variants, which may be rarer or regulatory. However, additional association tests yielded four significant PsychArray variants (SP110, rs181058279; AGBL2, rs76215382; SUCLA2, rs121908538; APH1B, rs745918508), raising the likelihood that these genes confer risk of completed suicide.

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 )w ere 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.

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.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.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.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.

When smokers were separated by their nicotinic receptor gene variants, those with the low-risk genotype responded equally well to pharmacological treatments, including both nicotine replacement and bupropion, and nonpharmacological therapies. Those with the high-risk genotype, as identified by DNA sequencing, responded only to pharmacological treatments. Clinicians advising patients on smoking cessation can suspect genetic risk on the basis of early onset of heavy smoking and direct those smokers specifically to pharmacological treatments.

Introduction Previous research revealed significant associations between haplotypes in the CHRNA5-A3-B4 subunit cluster and scores on the Fagerstrom 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.

Genetic studies of autism over the past decade suggest a complex landscape of multiple genes. In the face of this heterogeneity, studies that include large extended pedigrees may offer valuable insights, as the relatively few susceptibility genes within single large families may be more easily discerned. This genome-wide screen of 70 families includes 20 large extended pedigrees of 6-9 generations, 6 moderate-sized families of 4-5 generations and 44 smaller families of 2-3 generations. The Center for Inherited Disease Research (CIDR) provided genotyping using the Illumina Linkage Panel 12, a 6K single-nucleotide polymorphism (SNP) platform. Results from 192 subjects with an autism spectrum disorder (ASD) and 461 of their relatives revealed genome-wide significance on chromosome 15q, with three possibly distinct peaks: 15q13.1-q14 (heterogeneity LOD (HLOD)=4.09 at 29 459 872 bp); 15q14-q21.1 (HLOD=3.59 at 36 837 208 bp); and 15q21.1-q22.2 (HLOD=5.31 at 55 629 733 bp). Two of these peaks replicate earlier findings. There were additional suggestive results on chromosomes 2p25.3-p24.1 (HLOD=1.87), 7q31.31-q32.3 (HLOD=1.97) and 13q12.11-q12.3 (HLOD=1.93). Affected subjects in families supporting the linkage peaks found in this study did not reveal strong evidence for distinct phenotypic subgroups.

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 understand better the latent structure of dependence and to guide distillation of the phenotype. Using data from four samples of smokers (including treatment and non-treatment samples), latent profiles were derived using the Wisconsin Inventory of Smoking Dependence Motives (WISDM) subscale scores. Across all four samples, results revealed a unique latent profile that had relative elevations on four dependence motive subscales (Automaticity, Craving, Loss of Control, and Tolerance). Variable-centered analyses supported the uniqueness of these four subscales both as measures of a common factor distinct from that underlying the other nine subscales, and as the strongest predictors of relapse, withdrawal and other dependence criteria. Conversely, the remaining nine motives carried little unique predictive validity regarding dependence. Applications of a factor mixture model further support the presence of a unique class of smokers in relation to a common factor underlying the four subscales. The results illustrate how person-centered analyses may be useful as a supplement to variable-centered analyses for uncovering variables that are necessary and/or sufficient predictors of disorder criteria, as they may uncover small segments of a population in which the variables are uniquely distributed. The results also suggest that severe dependence is associated with a pattern of smoking that is heavy, pervasive, automatic and relatively unresponsive to instrumental contingencies.

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

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.

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.

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.

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.

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 occuring 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 factor structure and external validity of the Tridimensional Personality Questionnaire (TPQ) were examined in a sample of 303 male alcoholics in an inpatient treatment program. Confirmatory factor analyses did not support either the original tridimensional structure or the factor structures obtained in a nonclinical sample by Cloninger, Przybeck, and Svrakic (1991). An exploratory factor analysis suggested the TPQ comprises 5 factors: Subjective Distress, Detachment, Disinhibition, Relaxed Confidence, and Orderliness/Persistence. Each of the original scales was round to be multidimensional in terms of the 5 factors. The Novelty Seeking (NS) scale included most of the items of the Disinhibition factor scale, and the construct validity of both scales was supported by correlations with external measures of antisocial behavior and a measure of Cloninger 's Type 2 alcoholism

Finding predisposition genes for Autism Spectrum Disorder (ASD) has proven challenging, and new methods are needed to aid the process. Using pedigree structure as a strategy to identify ASD predisposition genes, we previously performed a genome-wide linkage scan of 86 selected families from the Autism Resource Exchange (AGRE) that appeared to inherit ASD in a dominant manner. We identified a suggestive linkage peak on chromosome Xp22.11-p21.2 that encompasses the IL1RAPL1 gene, a strong candidate gene for ASD. In this follow-up study, we sequenced the coding regions of the IL1RAPL1 gene in 14 male cases representing one case from each pedigree that showed at least nominal linkage evidence on per pedigree basis to the chromosome X region. We observed no deleterious mutations or deletions in the IL1RAPL1 gene in these 14 ASD cases. A SNP was identified in exon 2 in five cases and a variant of unknown significance was identified in intron 6 in a single case. In conclusion, coding changes of the IL1RAPL1 gene do not appear to be associated with ASD in selected AGRE families with linkage evidence to the chromosome Xp22.11-p21.2 region. Autism Res2011,4:293–296. © 2011 International Society for Autism Research, Wiley Periodicals, Inc.

Zhao et al. [2007] in their "Unified Theory of Autism" hypothesized that incidence of autism in males could be explained by essentially two types of family structures: majority of autism cases are from low-risk autism families with de novo mutations, and a minority of cases are from high-risk multiplex families, where risk to male offspring approximates 50% consistent with a dominant model and high penetrance. Using the Autism Genetic Resource Exchange (AGRE) data set, Zhao et al. identified 86 high-risk families with likely dominant transmission. As genotype data are now available for many members of the AGRE resource, the objective of this manuscript was to determine if dominant linkage evidence for an autism predisposition gene exists in these 86 high-risk families. HumanHap550K Illumina SNP data were available for 92% of 455 total family members in these 86 high-risk families. We performed a linkage analysis using a pruned subset of markers where markers in high linkage disequilibrium were removed. We observed a single suggestive peak (maximum LOD 2.01, maximum HLOD 2.08) under a dominant model on chromosome Xp22.11-p21.2 that encompasses the IL1RAPL1 gene. Mutations or deletions in IL1RAPL1 have been previously reported in three families with autism. In our study, 11 families contributed nominally (P0.05, HLOD0.588) to the chromosome X peak. These results demonstrate that identification of a more homogeneous subset of autism cases, which was based on family structure in this study, may help to identify, localize and further our understanding of autism predisposition genes.

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.

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.

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 factors 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.

The role of mood state (affect) and personality on basal acid secretion and basal serum gastrin concentrations were examined in seven healthy men and eight patients with duodenal ulcer. In each subject, gastric secretion and affect were assessed simultaneously on 5 separate days. None of 10 self-reported affect variables correlated with daily fluctuations in basal acid secretion in either group. Three variables (tension, conflict, and anxiety) correlated significantly with serum gastrin fluctuations in normal subjects, but these relationships were not present in patients with ulcer, who were hypergastrinemic regardless of their affective state. The degree to which serum gastrin fluctuated was unrelated to personality, as assessed by Minnesota Multiphasic Personality Inventory. On the other hand, several Minnesota Multiphasic Personality Inventory scales correlated with the degree of variability in basal acid secretion, including scales that measured impulsivity and social isolation/alienation. These studies indicate that serum gastrin concentrations are related to affective state in normal men, that this relationship is altered in men with duodenal ulcer, and that certain personality traits, such as impulsivity and social isolation, are associated with more labile basal acid secretion rates.

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 α and three β 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 = 2.0×10−5; 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., Author Summary Tobacco use is a global health care problem, and persistent smoking takes an enormous toll on individual health. The onset of daily smoking in adolescence is related to chronic use and severe nicotine dependence in adulthood. Since nicotine is the key addictive chemical in tobacco, we tested the hypothesis that genetic variants within nicotinic acetylcholine receptors will influence the severity of addiction measured in adulthood. Using genomic resequencing to define the patterns of variation found in these candidate genes, we observed that common haplotypes in the CHRNA5-A3-B4 gene cluster are associated with adult nicotine addiction, specifically among those who began daily smoking before age 17. We show that in populations of European origins, one haplotype is a risk factor for dependence, one is protective, and one is neutral. These observations suggest that genetic determinants expressed during human adolescence contribute to the risk of lifetime addiction severity produced from early onset of cigarette use. Because disease risk from the adverse health effects of tobacco smoke is related to lifetime tobacco exposure, the finding that an age-dependent effect of these haplotypes has a strong influence on lifetime smoking behavior reinforces the public health significance of delaying smoking onset.

Inpatients in Veterans Administration substance-abuse treatment programs voluntarily took the Minnesota Multiphasic Personality Inventory (MMPI) as part of a routine clinical evaluation

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.

An understanding of the strengths and limitations of automated data is valuable when using administrative or clinical databases to monitor and improve the quality of health care. This study discusses the feasibility and validity of using data electronically extracted from the Veterans Health Administration (VHA) computer database (VistA) to monitor guideline performance for inpatient and outpatient treatment of schizophrenia. The authors also discuss preliminary results and their experience in applying these methods to monitor antipsychotic prescribing using the South Central VA Healthcare Network (SCVAHCN) Data Warehouse as a tool for quality improvement.

Article-at-a-Glance Background Because most guidelines focus on patients with new episodes of depression, algorithms to identify such samples must be accurate. This study examined whether the Veterans Health Administration's (VHA's) electronic medical record database could identify valid cases of new-onset depression. Results Of 109 individuals receiving outpatient care at one of three VHA medical centers who were identified with newly diagnosed depressive disorder, 39 (35.8%) actually had documentation of depression diagnosis and antidepressant prescription or other treatment within the previous six months. Good to excellent agreement was found between indicators of guideline-concordant care using automated and manual chart review methods. Discussion Electronic medical records can validly identify many cases of new-onset depression, although with a higher-than-anticipated rate of false-positives. Half of depressed veterans received care consistent with clinical guidelines for psychopharmacological intervention, regardless of data source. Summary Clinical managers, administrators, and policy advocates must weigh the cost–benefit of administrative versus medical record reviews to assess quality.

The purpose of this study was to examine mental health care experts' opinions about performance measures and associated data elements that could serve as the basis of an information system for monitoring the implementation of clinical practice guidelines for major depressive disorder (MDD) and schizophrenia in the Veterans Health Administration (VHA). Nineteen mental health care experts rated the meaningfulness and validity of performance measures and automated data elements. For MDD, experts rated the following measures as very meaningful and valid: (a) the results of depression screening, (b) the occurrence and results of diagnostic assessment for MDD, (c) the provision of antidepressant medication or psychotherapy, and (d) whether antidepressant medications were prescribed within the therapeutic dose range recommended by practice guidelines. For schizophrenia, expert reviewers rated therapeutic doses of antipsychotic medication and assessment for antipsychotic medication side effects as being very meaningful and valid. Performance measures that evaluate clinically significant aspects of care using specific, valid data elements are the most meaningful. Translation efforts by the VHA's Mental Health Quality Enhancement Research Initiative program include additional studies of the validity of some of the proposed data elements and the development of national clinical reminders for performance measures judged to be meaningful.

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.

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 (1) contiguous to lithium-induced toxicosis, (2) novel, (3) more intense, and (4) 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.

Thirty rats were randomly assigned to three groups. Group 1 was given a 21-day exposure to an ethanol (EtOH) liquid diet, while Groups 2 and 3 were given equivalent amounts of an isocaloric non-EtOH liquid diet. Group 1 rats had withdrawal syndromes following EtOH removal. After a two-week recovery period, Groups 1 and 2 were both exposed to an EtOH diet, while Group 3 again received an isocaloric non-EtOH liquid diet. Groups 1 and 2 were withdrawn after 12 days of EtOH exposure and were rated with a behavioral withdrawal rating scale, for which interobserver reliability estimates were determined. Previously dependent (Group 1) rats showed more severe withdrawal syndromes, including a higher incidence of seizures, than rats undergoing their initial withdrawal (Group 2). Studies that do not agree with this finding are discussed.

Summary Aversion therapy for alcoholism is based on the notion that aversion conditioning produces a conditioned response (CR) to alcohol that is antagonistic to subsequent alcohol ingestion. This study reports the first experimental evidence that aversion conditioning produces a CR to the taste and smell of alcohol. Two patients were given taste aversion therapy for alcoholism. While medically conservative, the taste-aversion procedures produced profound malaise and reliable emesis shortly after patients began drinking alcoholic beverages. Behavioral. attitudinal and psychophysiological indices all reflected the acquisition of an alcohol aversion as a function of conditioning.

Pairing a familiar palatable fluid and a novel context with lithium chloride (LiCl) and presenting the fluid on non-LiCl-paired trials in the home cage resulted in contextual control of fluid consumption: consumption of the LiCl-paired fluid was reduced in the LiCl-paired context but not in the home cage. A nonpaired fluid was consumed normally in the paired context. These results are interpreted as evidence of occasion setting, i.e., the novel context signals a contingency between the fluid and toxicosis but is not itself associated with toxicosis. Pairing the novel context with LiCl prior to fluid-context-LiCl pairings enhanced the development of contextual control of consumption of the fluid. This enhancement is interpreted as summation of excitatory conditioning of the context with its occasion-setting function.

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.

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.

In Experiment 1 rats were gavaged with ethanol and nutrients at 6 hr intervals for 72 hr. Ethanol dosages were assigned by behavioral criteria of inebriation. Nourished animals were able to tolerate higher ethanol dosages than nutrient-deprived rats (9.62 vs 7.60 g/kg/day). Nourished rats were less likely to have withdrawal seizures than were nutrient-deprived rats given an equivalent amount of ethanol, but nourished rats given 25–30% more ethanol than the nutrient-deprived rats did have withdrawal seizures. Nutrient-deprived rats had BEC's (Blood Ethanol Contents) higher than those of nourished rats receiving equivalent amounts of ethanol but comparable to the BEC's of nourished rats receiving 25–30% more ethanol. All these results were replicated in Experiment 2 in which ethanol dependent rats above starting body weight were produced after only nine ethanol doses (54 hr).

Cette experience montre que la therapie aversive des alcooliques a pour effet de diminuer leur consommation dans les tests gustatifs, de rendre plus negatives leurs evaluations, d'induire des indicateurs d'aversion (grimace, par exemple) et d'augmenter leurs reponses tachycardiques

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.