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CORK Bibliography: Genetics and Drug Use

111 citations. July 2010 to present

Prepared: March 2012

Agrawal A; Scherrer JF; Lynskey MT; Sartor CE; Grant JD; Haber JR et al. Patterns of of use, sequence of onsets and correlates of tobacco and cannabis. Addictive Behaviors 36(12): 1141-1147, 2011. (48 refs.)

Background: While most individuals initiate their use of tobacco prior to onset of cannabis use, recent reports have identified a smaller subset of youth who report onset of cannabis use prior to tobacco use. In this study, we characterize patterns of cannabis and tobacco use (tobacco but not cannabis, cannabis but not tobacco or both) and compare the factors associated with onset of tobacco before cannabis and cannabis before tobacco. Methods: Data on 1812 offspring aged 12-32 years, drawn from two related offspring of Vietnam Era twin studies, were used. Individuals were divided into tobacco but not cannabis (T), cannabis but not tobacco (C) and users of both substances (CT). Those who used both could be further classified by the timing of onset of tobacco and cannabis use. Multinomial logistic regression was used to characterize the groups using socio-demographic and psychiatric covariates. Furthermore, data on parental smoking and drug use was used to identify whether certain groups represented greater genetic or environmental vulnerability. Results: 22% (N = 398) reported T, 3% (N = 55) reported C and 44% reported CT (N = 801). Of the 801 CT individuals, 72.8% (N = 583), 9.9% (N = 77) and 17.3% (N = 139) reported onset of tobacco before cannabis, cannabis before tobacco and onsets at the same age. C users were as likely as CT users to report peer drug use and psychopathology, such as conduct problems while CT was associated with increased tobacco use relative to T. Onset of tobacco prior to cannabis, when compared onset of cannabis before tobacco or reporting initiation at the same age was associated with greater cigarettes smoked per day, however no distinct factors distinguished the group with onset of cannabis before tobacco from those with initiation at the same age. Conclusion: A small subset of individuals report cannabis without tobacco use. Of those who use both cannabis and tobacco, a small group report cannabis use prior to tobacco use. Follow-up analyses that chart the trajectories of these individuals will be required to delineate their course of substance involvement.

Anokhin AP; Golosheykin S; Grant JD; Heath AC. Heritability of delay discounting in adolescence: A longitudinal twin study. Behavior Genetics 41(2): 175-183, 2011. (53 refs.)

Delay discounting (DD) refers to the preference for smaller immediate rewards over larger but delayed rewards, and is considered to be a distinct component of a broader "impulsivity" construct. Although greater propensity for discounting the value of delayed gratification has been associated with a range of problem behaviors and substance abuse, particularly in adolescents, the origins of individual differences in DD remain unclear. We examined genetic and environmental influences on a real-life behavioral measure of DD using a longitudinal twin design. Adolescent participants were asked to choose between a smaller ($7) reward available immediately and a larger ($10) reward to be received in 7 days. Biometrical genetic analysis using linear structural equation modeling showed significant heritability of DD at ages 12 and 14 (30 and 51%, respectively) and suggested that the same genetic factors influenced the trait at both ages. DD was significantly associated with symptoms of conduct disorder, attention deficit hyperactivity disorder, substance use, and with higher novelty seeking and poor self-regulation. This study provides the first evidence for heritability of DD in humans and suggests that DD can be a promising endophenotype for genetic studies of addiction and externalizing disorders.

Bailey JA; Hill KG; Meacham MC; Young SE; Hawkins JD. Strategies for characterizing complex phenotypes and environments: General and specific family environmental predictors of young adult tobacco dependence, alcohol use disorder, and co-occurring problems. Drug and Alcohol Dependence 118(2-3): 444-451, 2011. (61 refs.)

Background: Defining phenotypes in studies of tobacco and alcohol misuse is difficult because of the complexity of these behaviors and their strong association with each other and with other problem behaviors. The present paper suggests a strategy for addressing this issue by conceptualizing and partitioning variance in phenotypes into either general or substance/behavior-specific. The paper also applies the general or substance/behavior-specific conceptualization to environmental predictors of tobacco and alcohol misuse and other problem behaviors. Methods: Data were drawn from the Seattle Social Development Project, a contemporary, ethnically diverse and gender-balanced longitudinal panel including 808 participants. Latent variable modeling was used to partition variance in young adult (age 24) nicotine dependence, alcohol abuse and dependence, illicit drug abuse and dependence, involvement in crime, and engagement in HIV sexual risk behavior into general problem behavior and behavior-specific variance. Similarly, measures of general, drinking-specific, and smoking-specific adolescent family environment were constructed. Results: Consistent with expectations, more positive general family environment during adolescence was associated with lower levels of shared variance in problem behaviors at age 24, but not with unique variance in tobacco or alcohol use disorder. Higher levels of family smoking and drinking environments during adolescence, however, were positively associated with unique variance in tobacco and alcohol use disorder, respectively, but did not predict shared variance in problem behaviors. Conclusions: Results support the utility of the proposed approach. Ways in which this approach might contribute to future molecular genetic studies are discussed.

Baler RD; Volkow ND. Addiction as a systems failure: Focus on adolescence and smoking. (review). Journal of the American Academy of Child and Adolescent Psychiatry 50(4): 329-339, 2011. (115 refs.)

Objective: Scientific advances in the field of addiction have forever debunked the notion that addiction reflects a character flaw under voluntary control, demonstrating instead that it is a bona fide disease of the brain. The aim of this review is to go beyond this consensus understanding and explore the most current evidence regarding the vast number of genetic, developmental, and environmental factors whose complex interactions modulate addiction risk and trajectory. Method: Focusing on childhood and adolescent smoking as a paradigm, we review the important risk factors for the development of addictions, starting at the level of genetics and closing with a focus on sociocultural and policy factors. Results: A critical review of the pertinent literature provides a detailed view of the cumulative power of risk and protection factors across different phenomenological levels to modulate the risk of undesirable outcomes, particularly for young people. The result represents a compelling argument for the need to engage in comprehensive, multilevel approaches to promoting health. Conclusions: Today, the field of medicine understands more about disease than about health; however it need not be that way. The view of drug addiction as a systems failure should help refocus our general approach to developing dynamic models and early comprehensive interventions that optimize the ways in which we prevent and treat a complex, developmental disorder such as drug addiction.

Benko CR; Farias AC; Farias LG; Pereira EF; Louzada FM; Cordeiro ML. Potential link between caffeine consumption and pediatric depression: A case-control study. BMC Pediatrics 11: AR 73, 2011. (38 refs.)

Background: Early-onset depressive disorders can have severe consequences both from developmental and functional aspects. The etiology of depressive disorders is complex and multi-factorial, with an intricate interaction among environmental factors and genetic predisposition. While data from studies on adults suggest that caffeine is fairly safe, effects of caffeine in children, who are in period of rapid brain development, are currently unknown. Furthermore, systematic research addressing the relationship between depressive symptoms in children and caffeine consumption is lacking. The present study examined the effects of caffeine consumption on depressed mood in children with depression and non-depressed participants. Methods: Children and adolescents (n = 51) already enrolled in an ongoing longitudinal study, aged 9-12 years, were assessed for depressive symptoms with the Children Depressive Inventory (CDI). Psychopathological symptoms were assessed with the Child Behavioral Checklist (CBCL) and eating habits were assessed with the Nutrition-Behavior Inventory (NBI) [1]. The children were compared to control children without psychopathology attending public schools in a Southern Brazilian city. Results: Participants with CDI scores = 15 (mean = 19; S. D. = 4) also had high NBI scores (mean = 52; S. D. = 19, p < 0.001) suggestive of a relationship between depressive symptoms and environmental factors, in this case nutrition/behavior. Additional linear regression adjusted statistical analysis, considering the factors of consumption of sweets and caffeine individually, showed that caffeine, but not sweets, was associated with depressive symptoms. Conclusions: These findings indicate that depressed children consume more caffeinated drinks than non-depressed children. Nonetheless while a strong association between depressive symptoms and caffeine consumption among children was found, further research should investigate whether or not this association is due to a cause and effect relationship.

Benyamina A; Kebir O; Blecha L; Reynaud M; Krebs MO. CNR1 gene polymorphisms in addictive disorders: A systematic review and a meta-analysis. (review). Addiction Biology 16(1): 1-6, 2011. (37 refs.)

The aim of the present work was to systematically review all association studies of cannabis receptor 1 (CNR1) polymorphisms with dependence syndrome and to perform a meta-analysis. Odds ratios (ORs) were estimated by contrasting the ratio of counts of the 'high risk' versus 'low risk' alleles in cases with dependence versus controls. Studies were analyzed by random-effects meta-analysis using pooled OR. Eleven full text articles met our eligibility criteria and nine meta-analyses were performed on three polymorphisms of CNR1: rs1049353, rs806379 and the AAT repeat. Of these, only the AAT polymorphism showed a significant association with illicit substance dependence but only in the Caucasian population samples and using a risk allele definition of >= 16 repeats. Our analysis showed a small effect size (OR = 1.55, P = 0.045), with strong heterogeneity (Q = 19.87, P < 0.01 with I2 = 85%). In line with the polygenic model, our meta-analysis supports a minor implication for CNR1 AAT polymorphism in illicit substance dependence vulnerability. Further studies in well-phenotyped samples and using more polymorphisms are needed to conclude on the actual influence of cannabinoid receptor polymorphisms.

Bernow N; Kruck B; Pfeifer P; Lieb K; Tuscher O; Fehr C. Impulsiveness and venturesomeness in German smokers. Nicotine & Tobacco Research 13(8): 714-721, 2011. (64 refs.)

Introduction: Cigarette smoking is a behavior, which is influenced by genetic, demographic, and psychological factors. A large body of research has examined the association of cigarette smoking variables with individual differences in personality traits. The aim of the current study was to replicate the findings of higher self-reported impulsivity in smokers compared with never-smokers in a German sample using Eysenck's construct of impulsivity. Furthermore, it was intended to further the knowledge about associations between different self-reported impulsivity components and different smoking variables. Methods: We used the Impulsiveness-Venturesomeness-Empathy questionnaire (I7) to measure self-reported impulsiveness and venturesomeness and the Temperament and Character Inventory (TCI) to measure novelty seeking (NS) in a sample of 82 nicotine-dependent smokers and 119 never-smokers. Results: Smokers scored higher on impulsiveness, venturesomeness, and NS than never-smokers independent of age, gender, and years of education. We found a significant association between venturesomeness, impulsiveness and smoking status in daily smokers. Conclusions: In summary, this study provides evidence that impulsiveness and venturesomeness as well as the novelty-seeking subscale extravagance are significantly associated with smoking status in a German sample of female and male smokers compared with never-smokers.

Bienvenu OJ; Davydow DS; Kendler KS. Psychiatric 'diseases' versus behavioral disorders and degree of genetic influence. (review). Psychological Medicine 41(1): 33-40, 2011. (56 refs.)

Background. Psychiatric conditions in which symptoms arise involuntarily ('diseases') might be assumed to be more heritable than those in which choices are essential (behavioral disorders). We sought to determine whether psychiatric 'diseases' (Alzheimer's disease, schizophrenia, and mood and anxiety disorders) are more heritable than behavioral disorders (substance use disorders and anorexia nervosa). Method. We reviewed the literature for recent quantitative summaries of heritabilities. When these were unavailable, we calculated weighted mean heritabilities from twin studies meeting modern methological standards. Results. Heritability summary estimates were as follows : bipolar disorder (85 %), schizophrenia (81 %), Alzheimer's disease (75 %), cocaine use disorder (72 %), anorexia nervosa (60 %), alcohol dependence (56 %), sedative use disorder (51 %), cannabis use disorder (48 %), panic disorder (43 %), stimulant use disorder (40 %), major depressive disorder (37 %), and generalized anxiety disorder (28 %). Conclusions. No systematic relationship exists between the disease-like character of a psychiatric disorder and its heritability; many behavioral disorders seem to be more heritable than conditions commonly construed as diseases. These results suggest an error in 'common-sense' assumptions about the etiology of psychiatric disorders. That is, among psychiatric disorders, there is no close relationship between the strength of genetic influences and the etiologic importance of volitional processes.

Blum K; Liu YJ; Shriner R; Gold MS. Reward circuitry dopaminergic activation regulates food and drug craving behavior. (review). Current Pharmaceutical Design 17(12): 1158- 1167, 2011. (127 refs.)

Neural circuits implicated in drug conditioning, craving and relapse overlap extensively with those involved in natural reward and reinforcement like food. Exposure to drug-related cues in human addicts results in drug craving and localized activation of central circuits that are known to mediate cue-induced reinstatement of drug-seeking behavior in animal models of relapse. Similar regional activation patterns occur in humans in response to cues associated with foods. Furthermore, drug-and food-related cues not only activate common neuroanatomical regions but also result in similar activity-regulated gene expression programs within these shared areas. Cues predictive of food availability are powerful modulators of appetite as well as food-seeking and ingestive behaviors. The upregulation of a number of early genes in unique patterns within corticostriatal, thalamic, and hypothalamic networks suggests that food cues are capable of powerfully altering neuronal processing in areas mediating the integration of emotion, cognition, arousal, and the regulation of energy balance. The dopaminergic, enkephalinergic, and fos gene expressions are important regulatory genetic pathways for food craving behaviors. An umbrella term to describe common genetic antecedents of multiple impulsive, compulsive and addictive behaviors is Reward Deficiency Syndrome (RDS). Individuals possessing a paucity of serotonergic and/or dopaminergic receptors and an increased rate of synaptic dopamine catabolism, due to high catabolic genotype of the COMT gene, are predisposed to self-medicating any substance or behavior that will activate dopamine release including alcohol, opiates, psychostimulants, nicotine, glucose, gambling, sex, and even excessive internet gaming, among others. Finally, utilizing the long term dopaminergic activation approach will ultimately lead to a common safe and effective modality to treat RDS behaviors including aberrant food and drug craving behaviors.

Boardman JD; Blalock CL; Pampel FC; Hatemi PK; Heath AC; Eaves LJ. Population composition, public policy, and the genetics of smoking. Demography 48(4): 1517-1533, 2011. (40 refs.)

In this article, we explore the effect of public policy on the extent to which genes influence smoking desistance. Using a sample of adult twins (n (mz) = 363, n (dz) = 233) from a large population registry, we estimate Cox proportional hazards models that describe similarity in the timing of smoking desistance among adult twin pairs. We show that identical twin pairs are significantly more likely to quit smoking within a similar time frame compared with fraternal twin pairs. Importantly, we then show that genetic factors for smoking desistance increase in importance following restrictive legislation on smoking behaviors that occurred in the early and mid-1970s. These findings support the social push perspective and make important contributions to the social demography and genetic epidemiology of smoking as well as to the gene-environment interaction literatures.

Breitling LP; Muller H; Illig T; Rujescu D; Winterer G; Dahmen N et al. Dopamine-related genes and spontaneous smoking cessation in ever-heavy smokers. Pharmacogenomics 12(8): 1099-1106, 2011. (32 refs.)

Several studies have provided evidence for associations of polymorphisms located in and near dopamine-related genes and nicotine dependence and other smoking-related phenotypes, including pharmacogenetic interactions. Aim: The purpose of the present work was to examine the association of SNPs in the DOPA decarboxylase (DDC), dopamine receptor D2 (DRD2) and dopamine transporter (SLC6A3) genes with smoking cessation in a large retrospective study featuring approximately 900 cessation events. Materials & methods: Data originated from the enrollment questionnaire of the epidemiological ESTHER study of community-dwelling adults aged 50-74 years, conducted in the German state of Saarland between July 2000 and December 2002. Restricting the analyses to subjects who reported to have regularly smoked >20 cigarettes per day at some point in their life, we used survival ana-lysis methods to model the time from initiation of regular smoking to cessation (defined as quitting with abstinence lasting until enrollment) and its relation with eight polymorphisms in the aforementioned genes (five in DDC, two in DRD2 and one in SLC6A3) in 1446 participants. Results: Neither individual variants nor DDC haplotypes were associated with the probability of overcoming nicotine dependence in this cohort. Conclusion: The repeated suggestion of associations between the variants examined and nicotine dependence in previous reports seems to contrast the negative results in the present study. This would appear consistent with the hypothesis that the establishment of regular heavy smoking might abolish associations between genetic determinants of nicotine dependence and nicotine dependence-related phenotypes, in particular the probability of successful smoking cessation.

Brock AJ; Takeda A; Brennan C; Walton RT. Treatment for tobacco dependence: A potential application for stratified medicine? (review). Personalized Medicine 8(5): 571-579, 2011. (70 refs.)

Tobacco addiction is a leading preventable cause of death worldwide and places a heavy social and financial burden on society. Therefore, ways of helping people to overcome nicotine dependence are a key element of strategies aimed at improving public health. Current treatments are only partially effective and there is a need to develop more efficient approaches to help smokers to stop. There exists a substantial genetic variability in smoking behavior and the likelihood of cessation - tailoring treatment according to an individual's genetic profile is now technologically feasible and could lead to more successful cessation attempts. Here we review studies of the genetic effects on smoking cessation in randomized controlled trials of pharmacological therapy and discuss the potential value of a personalized approach to help people stop smoking.

Broms U; Kaprio J; Hublin C; Partinen M; Madden PAF; Koskenvuo M. Evening types are more often current smokers and nicotine-dependent-a study of Finnish adult twins. Addiction 106(1): 170-177, 2011. (42 refs.)

Aims: To examine the association between diurnal type and smoking status and nicotine dependence (ND). Design: A cohort study using random-effects model regressions for repeated longitudinal panel data was used to analyse smoking status by diurnal type. Regression analyses examined the association between diurnal type and ND. Participants: A total of 23 289 same-sex adult twin individuals from Finnish Twin Cohort. Nicotine dependence was studied in a subsample of 676 twin individuals. Measurements: Subjects were classified by self-report into four categories: morning type, somewhat morning type, somewhat evening type, evening type (in 1981). Smoking status was defined as current and ever smoking (in 1975, 1981 and 1990). ND was measured by DSM-IV and Fagerstrom Test for Nicotine Dependence (FTND) (during 2001-05). Findings: Evening types of both genders were much more likely to be current (OR = 2.91, 95% CI 2.50, 3.38) and life-time smokers (OR = 2.67, 95% CI 2.96, 4.07) compared to morning types. Evening types were less likely to stop smoking. The risk of nicotine dependence assessed by DSM-IV criteria was higher among evening types (OR = 2.78, 95% CI 1.64, 4.72). Evening types scored 0.59 (95% CI 0.01, 1.17) points higher than morning types on the FTND. Adjustment for potential confounders did not change these associations. Conclusions: Being an evening type is associated independently with a higher risk of being a current smoker, being more highly dependent upon cigarettes and a lower likelihood of stopping smoking. Understanding the cause of these associations could elucidate the causes of tobacco addiction.

Bunten H; Liang WJ; Pounder D; Seneviratne C; Osselton MD. CYP2B6 and OPRM1 gene variations predict methadone-related deaths. Addiction Biology 16(1): 142-144, 2011. (17 refs.)

The largest proportion of methadone-associated deaths occurs during the drug induction phase. We analysed methadone-related fatalities for gene variations linked with methadone action. A significant association between high methadone concentrations and the CYP2B6*6 allele characteristic of the slow metabolizer phenotype was identified. We suggest that the risk of methadone fatality may be predetermined in part by the CYP2B6*6 allele. A significant correlation was also observed between post-mortem benzodiazepine concentrations and the OPRM1 A118G allele GA in methadone-related fatalities. Screening for these susceptibility variations prior to methadone prescription could assist in reducing the potential for serious adverse effects.

Carlsten C; Halperin A; Crouch J; Burke W. Personalized medicine and tobacco-related health disparities: Is there a role for genetics? (editorial). Annals of Family Medicine 9(4): 366-371, 2011. (69 refs.)

Genetic testing has been proposed as a means to increase smoking cessation rates and thus reduce smoking prevalence. To understand how that might be practically possible, with appreciation of the current social context of tobacco use and dependence, we performed a contextual analysis of smoking-related genetics and smoking cessation. To provide added value, genetics would need to inform and improve existing interventions for smokers (including behavioral and pharmacological treatments). Pharmacogenetics offers the most promising potential, because it may improve the efficacy of medication-based smoking cessations strategies. All proven interventions for treating tobacco dependence, however, including simple cost-effective measures, such as quit lines and physician counseling, are underutilized. As tobacco use occurs disproportionately among disadvantaged populations, efforts to improve smokers' access to health care, and to the tools that are known to help them quit, represent the most promising approaches for reducing smoking prevalence within these groups. Similar considerations apply to other chronic diseases contributing to population-level health disparities. We conclude that although genetics offers increasing opportunities to tailor drug treatment, and may in some cases provide useful risk prediction, other methods of personalizing care are likely to yield greater benefit to populations experiencing health disparities related to tobacco use.

Castaldi PJ; Demeo DL; Hersh CP; Lomas DA; Soerheim IC; Gulsvik A et al. Impact of non-linear smoking effects on the identification of gene-by-smoking interactions in COPD genetics studies. Thorax 66(10): 903-909, 2011. (19 refs.)

Background: The identification of gene-by-environment interactions is important for understanding the genetic basis of chronic obstructive pulmonary disease (COPD). Many COPD genetic association analyses assume a linear relationship between pack-years of smoking exposure and forced expiratory volume in 1 s (FEV(1)); however, this assumption has not been evaluated empirically in cohorts with a wide spectrum of COPD severity. Methods The relationship between FEV(1) and pack-years of smoking exposure was examined in four large cohorts assembled for the purpose of identifying genetic associations with COPD. Using data from the Alpha-1 Antitrypsin Genetic Modifiers Study, the accuracy and power of two different approaches to model smoking were compared by performing a simulation study of a genetic variant with a range of gene-by-smoking interaction effects. Results: Non-linear relationships between smoking and FEV(1) were identified in the four cohorts. It was found that, in most situations where the relationship between pack-years and FEV(1) is non-linear, a piecewise linear approach to model smoking and gene-by-smoking interactions is preferable to the commonly used total pack-years approach. The piecewise linear approach was applied to a genetic association analysis of the PI*Z allele in the Norway Case-Control cohort and a potential PI*Z-by-smoking interaction was identified (p=0.03 for FEV(1) analysis, p=0.01 for COPD susceptibility analysis). Conclusion: In study samples of subjects with a wide range of COPD severity, a non-linear relationship between pack-years of smoking and FEV1 is likely. In this setting, approaches that account for this non-linearity can be more powerful and less biased than the more common approach of using total pack-years to model the smoking effect.

Chan G; Gelernter J; Oslin D; Farrer L; Kranzler HR. Empirically derived subtypes of opioid use and related behaviors. Addiction 106(6): 1146- 1154, 2011. (37 refs.)

Aims: To identify and validate homogeneous subtypes of opioid use and related behaviors. Design: Family-based and case-control genetic studies of opioid and/or cocaine dependence. Settings: Clinical and general community samples from Connecticut, Massachusetts, Pennsylvania and South Carolina. Participants: A total of 4061 individuals (2003 individuals from 835 families and 2058 unrelated individuals) recruited to participate in genetic studies. Measurements: The computer-assisted Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA) was used to assess participants' demographics, medical history, substance use behaviors and disorders and other psychiatric disorders. Findings: Five homogeneous subtypes were identified, which differed on opioid-related measures, demographics and prevalence rates of substance use and psychiatric disorders. Heritability estimates for the two most severely affected subtypes exceeded 0.60. Conclusions: An empirical approach based on opioid use and related behaviors can yield homogeneous subtypes that could be of value in gene finding for opioid dependence.

Chen TJH; Blum K; Chen ALC; Bowirrat A; Downs WB; Madigan MA et al. Neurogenetics and clinical evidence for the putative activation of the brain reward circuitry by a neuroadaptagen: Proposing an addiction candidate gene panel map. Journal of Psychoactive Drugs 43(2): 108-127, 2011. (104 refs.)

This document presents evidence supporting the role of the KB220/KB220Z neuroadaptagens consisting of amino-acid neurotransmitter precursors and enkephalinase-catecholamine methyl transferase (COMT) inhibition therapy called Neuroadaptagen Amino Acid Therapy (NAAT) in brain reward function. It is becoming increasingly clear that this novel formulation is the first neuroadaptagen known to activate the brain reward circuitry. Ongoing research repeatedly confirms the numerous clinical effects that ultimately result in significant benefits for victims having genetic antecedents for all addictive, compulsive and impulsive behaviors. These behaviors are correctly classified under the rubric of "Reward Deficiency Syndrome" (RDS). We are proposing a novel addiction candidate gene map. We present preliminary findings in the United States using qEGG and in China using Functional Magnetic Resonance Imaging (fMRI) regarding the effects of oral NAAT on the activation of brain reward circuitry in victims of SUD. In unpublished data utilizing an fMRI 2X2 design at resting state, NAAT in comparison to placebo shows activation of the caudate brain region and potentially a smoothing out of heroin-induced putamen (a site for emotionality) abnormal connectivity. Although awaiting final analysis, if confirmed by ongoing studies in China coupled with published qEEG results in America, showing an increase in alpha and low beta, NAAT may be shown to impact treatment outcomes.

Chen XG; Abdulhamid I; Woodcroft K. Maternal smoking during pregnancy, polymorphic CYP1A1 and GSTM1, and lung-function measures in urban family children. Environmental Research 111(8): 1215-1221, 2011. (65 refs.)

Purpose: Understanding the interplay between genes and in-utero tobacco exposure in affecting child lung development is of great significance. In this study, we tested the hypothesis that tobacco-related lung-function reduction in children differs by maternal polymorphic genes Cytochrome P450 1A1 (CYP1A1) and Glutathione S-transferase Mu 1 (GSTM1). Materials and methods: Data were collected among 370 children (6-10 years old, 81.6% African-Americans) and their biological mothers visiting a large children's hospital. Study hypotheses were tested using multiple regression method. Results: Among the study sample, 143 mothers smoked throughout pregnancy and 72 smoked on a daily basis. Spirometric measures (mean +/- SD) included were: forced vital capacity(FVC)=1635 +/- 431 mL, forced expiratory volume in the first 1 s (FEV(1))=1440 +/- 360 mL, percent FEV(1)/FVC ratio=89 +/- 12, and forced expiratory flow between the 25% and 75% of PVC (FEF(25-75))=1745 +/- 603 mL In addition to a tobacco effect on FVC (-131 mL, 95% Cl: -245, -17) and FEV(1)/FVC ratio (42, 95% Cl: 1,83), regression analysis controlling for covariates indicated that for the subsample of children whose mothers were CYP1A1*2A homozygous, maternal daily smoking was associated with -734 mL (95% Cl: -1206, -262) reductions in FEV(1) and -825 mL (95% Cl: -909, -795) reductions in PVC; reduced smoking was still associated with -590 mL (95% CI: -629, -551) reductions in PVC. For children of mothers with GSTM1 deletion, persistent daily smoking was associated with -176 mL (95% CI: -305, -47) reductions in FVC. Discussion and conclusions: Maternal smoking during pregnancy was significantly associated with lung-function reduction in children, particularly for those whose mothers possessed the polymorphic CYP1A1*2A and GSTM1 deletion.

Chu CJ; Yang YC; Wei JX; Zhang L. Association of nicotinic acetylcholine receptor subunit alpha-4 polymorphisms with smoking behaviors in Chinese male smokers. Chinese Medical Journal 124(11): 1634-1638, 2011. (34 refs.)

Background It has been reported that the nicotinic acetylcholine receptor subunit alpha 4 gene (CHRNA4) might be associated with smoking behaviors in the previous studies. Up to now, there are few reports on the relationship between CHRNA4 and smoking initiation. In this study, we tried to explore the role of two polymorphisms in CHRNA4 (rs1044396 and rs1044397) in smoking initiation and nicotine dependence in Chinese male smokers. Methods. Nine hundred and sixty-six Chinese male lifetime nonsmokers and smokers were assessed by the Fagerstrom test for nicotine dependence (FTND), smoking quantity (SO) and the heaviness of smoking index (HSI). All subjects were divided into four groups based on their tobacco use history and the FTND scores. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed to find two polymorphisms of CHRNA4 in these subjects. Results. The X-2 test showed that rs1044396 was significantly associated with smoking initiation (X-2=4.65, P=0.031), while both rs1044396 and rs1044397 were significantly associated with nicotine dependence (X-2=5.42, P=0.020; X-2=7.58, P=0.005). Furthermore, the T-G (3.9%) haplotype of rs1044396-rs1044397 showed significant association with smoking initiation (X-2=6.30, P=0.012) and the C-G haplotype (58.9%) remained positive association with nicotine dependence (X-2=8.64, P=0.003) after Bonferroni correction. The C-G haplotype also significantly increased the HSI (P=0.002) and FTND scores (P=0.001) after Bonferroni correction. Conclusion. These findings suggest that CHRNA4 may be associated with smoking initiation and the C-G haplotype of rs1044396-rs1044397 might increase the vulnerability to nicotine dependence in Chinese male smokers.

Creemers HE; Harakeh Z; Dick DM; Meyers J; Vollebergh WAM; Ormel J et al. DRD2 and DRD4 in relation to regular alcohol and cannabis use among adolescents: Does parenting modify the impact of genetic vulnerability? The TRAILS study. Drug and Alcohol Dependence 115(1-2): 35- 42, 2011. (70 refs.)

Aims: The aims of the present study were to determine the direct effect of DRD2 and DRD4, as well as their interaction with parenting (i.e. rejection, overprotection and emotional warmth), on the development of regular alcohol and cannabis use in 1192 Dutch adolescents from the general population. Methods: Information was obtained by self-report questionnaires. Perceived rejection, overprotection and emotional warmth were assessed at age 10-12. Regular alcohol and cannabis use were determined at age 15-18 and defined as the consumption of alcohol on 10 or more occasions in the past four weeks, and the use of cannabis on 4 or more occasions in the past four weeks. Models were adjusted for age, sex, parental alcohol or cannabis use, and externalizing behavior. Results: Carrying the A1 allele of the DRD2 TaqIA polymorphism, or the 7 repeat DRD4, was not directly related to regular alcohol or cannabis use. In addition, adolescent carriers of these genetic risk markers were not more susceptible to the influence of less optimal parenting. Main effects for parenting indicated that overprotection increased the risk of regular alcohol use, whereas the risk of cannabis use was enhanced by parental rejection and buffered by emotional warmth. Conclusions: Our findings do not support an association between DRD2/DRD4 and regular alcohol and cannabis use in adolescents. Given the substance-specific influences of rejection, overprotection and emotional warmth, these parenting factors might be promising candidates for prevention work.

Cuyas E; Verdejo-Garcia A; Fagundo AB; Khymenets O; Rodriguez J; Cuenca A et al. The influence of genetic and environmental factors among MDMA users in cognitive performance. PLoS ONE 6(11): e27206, 2011. (56 refs.)

This study is aimed to clarify the association between MDMA cumulative use and cognitive dysfunction, and the potential role of candidate genetic polymorphisms in explaining individual differences in the cognitive effects of MDMA. Gene polymorphisms related to reduced serotonin function, poor competency of executive control and memory consolidation systems, and high enzymatic activity linked to bioactivation of MDMA to neurotoxic metabolites may contribute to explain variations in the cognitive impact of MDMA across regular users of this drug. Sixty ecstasy polydrug users, 110 cannabis users and 93 non-drug users were assessed using cognitive measures of Verbal Memory (California Verbal Learning Test, CVLT), Visual Memory (Rey-Osterrieth Complex Figure Test, ROCFT), Semantic Fluency, and Perceptual Attention (Symbol Digit Modalities Test, SDMT). Participants were also genotyped for polymorphisms within the 5HTT, 5HTR2A, COMT, CYP2D6, BDNF, and GRIN2B genes using polymerase chain reaction and TaqMan polymerase assays. Lifetime cumulative MDMA use was significantly associated with poorer performance on visuospatial memory and perceptual attention. Heavy MDMA users (> 100 tablets lifetime use) interacted with candidate gene polymorphisms in explaining individual differences in cognitive performance between MDMA users and controls. MDMA users carrying COMT val/val and SERT s/s had poorer performance than paired controls on visuospatial attention and memory, and MDMA users with CYP2D6 ultra-rapid metabolizers performed worse than controls on semantic fluency. Both MDMA lifetime use and gene-related individual differences influence cognitive dysfunction in ecstasy users.

Dick DM. Gene-environment interaction in psychological traits and disorders. (review). Annual Review of Clinical Psychology 7: 383-409, 2011. (111 refs.)

There has been an explosion of interest in studying gene-environment interactions (GxE) as they relate to the development of psychopathology. In this article, I review different methodologies to study gene-environment interaction, providing an overview of methods from animal and human studies and illustrations of gene-environment interactions detected using these various methodologies. Gene-environment interaction studies that examine genetic influences as modeled latently (e.g., from family, twin, and adoption studies) are covered, as well as studies of measured genotypes. Importantly, the explosion of interest in gene-environment interactions has raised a number of challenges, including difficulties with differentiating various types of interactions, power, and the scaling of environmental measures, which have profound implications for detecting gene-environment interactions. Taking research on gene-environment interactions to the next level will necessitate close collaborations between psychologists and geneticists so that each field can take advantage of the knowledge base of the other.

Dingel MJ; Karkazis K; Koenig BA. Framing nicotine addiction as a "disease of the brain": Social and ethical consequences. Social Science Quarterly 92(5): 1363-1388, 2011. (122 refs.)

Objectives. In this article, we seek to better understand how a genomic vision of addiction may influence drug prevention and treatment. Though social influences on substance use and abuse (e. g., peer and family influence, socioeconomic status) are well documented, biomedical intervention is becoming increasingly technoscientific in nature. We wish to elucidate how emphasizing biological influences on substance use may lead to a vision of addiction as a phenomenon isolated within our bodies and neurochemistry, not lived daily within a complex social web of relationships and a particular political economy, including the tobacco industry, which aggressively markets products known to cause harm. Methods. We explore the emerging view of addiction as a "disease of the brain" in open-ended interviews with 86 stakeholders from the fields of nicotine research and tobacco control. Interview data were analyzed using standard qualitative techniques. Results. Most stakeholders hold a medicalized view of addiction. Though environmental variables are understood to be a primary cause of smoking initiation, the speed and strength with which addiction occurs is understood to be a largely biological process. Though stakeholders believe that an increased focus on addiction as a disease of the brain is not likely to lead to widespread unrealistic expectations for cessation therapies, they remain concerned that it may reinforce teenagers' expectations that quitting is not difficult. Finally, stakeholder responses indicate that genetic and neuroscientific research is unlikely to increase or decrease stigmatization, but will be used by interest groups to buttress their existing views of the stigma associated with smoking. Conclusion. We argue that the main potential harms of focusing on biological etiology stem from a concept of addiction that is disassociated from social context. Focusing on genetic testing and brain scans may lead one to overemphasize pharmaceutical "magic bullet cures" and underemphasize, and underfund, more traditional therapies and public health prevention strategies that have proven to be effective. Genetic research on addiction may fundamentally change our conception of deviance and our identities, and may thus transform our susceptibility to substance use into something isolated in our biology, not embedded in a biosocial context.

Distel MA; Vink JM; Bartels M; van Beijsterveldt CEM; Neale MC; Boomsma DI. Age moderates non-genetic influences on the initiation of cannabis use: A twin-sibling study in Dutch adolescents and young adults. Addiction 106(9): 1658-1666, 2011. (26 refs.)

Aims To examine the heritability of cannabis initiation, the influence of a possible twin-specific environment and the influence of age on the effects of genes and environment in Dutch adolescents and young adults. Design Genetic structural equation modelling was used to partition the variance in the liability to cannabis initiation into genetic and environmental components. Setting All participants were registered with the Netherlands Twin Register. Participants A total of 6208 twins (age 13-20) and 1545 siblings (age 11-25) from 3503 families participated in this study. Measurements Self-reported cannabis use was assessed prospectively with the Dutch Health Behavior Questionnaire. Findings At the median age of the sample (16.5), genetic factors explained 40% of the individual differences in liability to cannabis initiation. Twins resembled each other more than non-twin siblings, which could not be attributed to the age difference between non-twin siblings. Environmental influences increased with age. This increase applied to environmental factors shared by twins (47% of the variance), environmental factors shared by twins and siblings (24%) and environmental factors unique to an individual (13%). Conclusion: The heritability of the liability for cannabis initiation is higher in adolescents than in young adults due to a larger contribution of environmental factors in young adults. This is due mainly to environmental factors only shared by twins and those shared by all offspring growing up in the same family, but the contribution of environmental factors specific to individuals is also larger in young adults.

Edge PJ; Gold MS. Drug withdrawal and hyperphagia: Lessons from tobacco and other drugs. (review). Current Pharmaceutical Design 17(12): 1173- 1179, 2011. (76 refs.)

'Globesity' is a descriptive term for the obesity epidemic now facing the U. S. and indeed, the world. Hyperphagia (i.e. overeating) can lead to metabolic syndrome which in turn can lead to Type 2 diabetes mellitus, heart disease, stroke and some cancers. The World Health Organization even states that more people die each year from the consequences of obesity than from hunger. Something must be done to stem the tsunami of obesity and its resultant medical complications. Our work and that of others suggests that new obesity treatments and anti-obesity medications should be based on those already successful in treating other addictions. This paper looks at empirical evidence linking addictions to food and to drugs such as tobacco, alcohol, cannabis, amphetamines, and cocaine. Hypotheses are put forth as to why hyperphagia is so difficult to treat. Additionally, prenatal programming for addiction is explored. Lessons from successful drug treatment are elucidated and potential pharmaceutical targets for hyperphagia and obesity are suggested.

Edwards AC; Maes HH; Pedersen NL; Kendler KS. A population-based twin study of the genetic and environmental relationship of major depression, regular tobacco use and nicotine dependence. Psychological Medicine 41(2): 395-405, 2011. (32 refs.)

Background. Numerous epidemiological studies have reported a positive association between major depression (MD) and regular tobacco use (RU) or nicotine dependence (ND). However, few have used a genetically informative design to assess whether these traits share a common genetic and/or environmental liability. Method. We assessed MD, RU and ND in same-sex twins from the population-based Swedish Twin Registry. In males, we examined both cigarette use and snus (smokeless tobacco) use. We used structural equation modeling to examine the relationship between MD, RU, and ND given RU. Results. The results suggest modest correlations between MD and RU, and between MD and ND. In males, the liability shared between MD and RU is solely genetic for both cigarettes and snus, while MD and ND share both genetic and unique environmental influences. The continuation to ND given RU differed considerably between cigarette and snus users. In females, both MD-RU and MD-ND relationships are partially attributable to genetic and unique environmental correlations. Conclusions. The relationship among MD, RU and ND is at least partially attributable to shared genetic and environmental risk factors. The genetic and environmental correlations between traits are modest. The nature of the shared liability differs by sex, and in males, by the type of tobacco product used. Differences between previous reports and results presented in the current study are suggestive of population differences in how MD and tobacco use inter-relate.

Ehlers CL; Gizer IR; Gilder DA; Wilhelmsen KC. Linkage analyses of stimulant dependence, craving, and heavy use in American Indians. American Journal of Medical Genetics. Part B: Neuropsychiatric Genetics 156B(7): 772-780, 2011. (115 refs.)

Amphetamine-type substances are the second most widely used illicit drugs in the United States. There is evidence to suggest that stimulant use (cocaine and methamphetamine) has a heritable component, yet the areas of the genome underlying these use disorders are yet to be identified. This study's aims were to map loci linked to stimulant dependence, heavy use, and craving in an American Indian community at high risk for substance dependence. DSM diagnosis of stimulant dependence, as well as indices of stimulant "craving," and "heavy use," were obtained using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA). Genotypes were determined for a panel of 791 micro-satellite polymorphisms in 381 members of multiplex families using SOLAR. Stimulant dependence, stimulant "craving," and "heavy stimulant use," were all found to be heritable. Analyses of multipoint variance component LOD scores, failed to yield evidence of linkage for stimulant dependence. For the stimulant "craving" phenotype, linkage analysis revealed a locus that had a LOD score of 3.02 on chromosome 15q25.3-26.1 near the nicotinic receptor gene cluster. A LOD score of 2.05 was found at this same site for "heavy stimulant use." Additional loci with LOD scores above 2.00 were found for stimulant "craving" on chromosomes 12p13.33-13.32 and 18q22.3. These results corroborate the importance of "craving" as an important phenotype that is associated with regions on chromosome 12, 15, and 18, that have been highlighted in prior segregation studies in this and other populations for substance dependence-related phenotypes.

Estrada G; Fatjo-Vilas M; Munoz MJ; Pulido G; Minano MJ; Toledo E et al. Cannabis use and age at onset of psychosis: Further evidence of interaction with COMT Val158Met polymorphism. Acta Psychiatrica Scandinavica 123(6): 485- 492, 2011. (69 refs.)

Objective: To examine, in a sample of young psychiatric patients, (n = 157, mean age 17.01 years (SD = 3.6)) whether i) age at first cannabis use and age at emergence of psychiatric disorders are related and ii) such a relationship is modulated by the Val158Met polymorphism in the COMT gene. Method: Cannabis use profiles and COMT Val158Met genotypes were obtained from 80 inpatients with schizophrenia-spectrum disorders and 77 inpatients with other non-psychotic disorders. Results: First, age at first cannabis use correlates with age at onset in both schizophrenia-spectrum and other psychiatric disorder groups: those who started using cannabis earlier had an earlier age at onset of psychiatric disorders. Second, the distribution of the Val158Met genotypes was not different either between diagnosis groups or between cannabis users and non-users. Third, an interaction between Val158Met genotypes and cannabis use was observed specifically on age at emergence of psychotic disorders, with Val/Val genotype carriers showing an earlier age at onset than Met carriers. Conclusion: Our results suggest the importance of brain maturation timing in which exposure to cannabis occurs. The COMT Val158Met genotype seems to modulate the association between cannabis and age at onset of psychotic disorders. These results are consistent with previous studies.

Falcone M; Jepson C; Sanborn P; Cappella JN; Lerman C; Strasser AA. Association of BDNF and COMT genotypes with cognitive processing of anti-smoking PSAs. Genes, Brain and Behavior 10(8): 862-867, 2011. (52 refs.)

Anti-smoking public service announcements (PSAs) often use persuasive arguments to attempt to influence attitudes about smoking. The persuasiveness of a PSA has previously been associated with factors that influence the cognitive processing of its message. Genetic factors that influence cognitive processing might thus affect individuals' responses to the persuasive arguments presented in PSAs. In the present study, we examined polymorphisms in the genes encoding brain-derived neurotrophic factor (BDNF Val66Met) and catechol-O-methyltransferase (COMT Val158Met), which affect cognitive processing in the prefrontal cortex, to identify genetic factors associated with self-reported outcomes of message processing, perceived effectiveness and quitting intentions among smokers viewing PSAs. A total of 120 smokers viewed sets of four PSAs that varied with respect to features of argument strength (AS) and message sensation value. We observed significant associations of BDNF genotype with central processing, narrative processing, perceived effectiveness of the anti-smoking PSAs and participant quitting intentions; the BDNF Met allele was associated with lower scores on all these measures. Central processing acted as a mediator of the association of genotype with quitting intentions and perceived effectiveness. There was a significant interaction of COMT genotype by AS in the model of narrative processing, such that individuals homozygous for the COMT Val allele reported higher narrative processing in the high-AS condition but not in the low-AS condition. To our knowledge, this is the first study to identify genetic factors associated with cognitive processing of anti-smoking PSAs.

Flory JD; Pytte CL; Hurd Y; Ferrell RE; Manuck SB. Alcohol dependence, disinhibited behavior and variation in the prodynorphin gene. Biological Psychology 88(1): 51-56, 2011. (43 refs.)

The results of the current analyses present preliminary evidence of an association between putatively functional variation in the prodynorphin (PDYN) gene and a dimensional measure of disinhibited behavior. A 68 bp sequence in the core promoter region of the PDYN gene was genotyped in a community sample of 1021 adults aged 30-54. Participants were interviewed for lifetime history of DSM-IV alcohol dependence and completed two self-report measures of sensation seeking and impulsiveness. Fifteen percent (n = 151) of the sample met DSM-IV criteria for alcohol dependence and while results did not support an association between the PDYN polymorphism and the diagnosis of alcohol dependence, we did observe an association between the "low" expressing L allele of the PDYN gene and a preference for engaging in disinhibited behavior. Additionally, people who had both a history of alcohol dependence and higher scores on this Disinhibited Behavior scale were most likely to carry an L allele. These results indicate that variation in the PDYN gene is associated with a dimensional trait or intermediate phenotype that reflects a preference for heavy drinking and engaging in related risky behaviors (e.g., drug use, sexual activity).

Fonseca F; de la Torre R; Diaz L; Pastor A; Cuyas E; Pizarro N et al. Contribution of cytochrome P450 and ABCB1 genetic variability on methadone pharmacokinetics, dose requirements, and response. PLoS ONE 6(5): e19527, 2011. (76 refs.)

Although the efficacy of methadone maintenance treatment (MMT) in opioid dependence disorder has been well established, the influence of methadone pharmacokinetics in dose requirement and clinical outcome remains controversial. The aim of this study is to analyze methadone dosage in responder and nonresponder patients considering pharmacogenetic and pharmacokinetic factors that may contribute to dosage adequacy. Opioid dependence patients (meeting Diagnostic and Statistical Manual of Mental Disorders, [4(th) Edition] criteria) from a MMT community program were recruited. Patients were clinically assessed and blood samples were obtained to determine plasma concentrations of (R, S)-, (R) and (S)-methadone and to study allelic variants of genes encoding CYP3A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, and P-glycoprotein. Responders and nonresponders were defined by illicit opioid consumption detected in random urinalysis. The final sample consisted in 105 opioid dependent patients of Caucasian origin. Responder patients received higher doses of methadone and have been included into treatment for a longer period. No differences were found in terms of genotype frequencies between groups. Only CYP2D6 metabolizing phenotype differences were found in outcome status, methadone dose requirements, and plasma concentrations, being higher in the ultrarapid metabolizers. No other differences were found between phenotype and responder status, methadone dose requirements, neither in methadone plasma concentrations. Pharmacokinetic factors could explain some but not all differences in MMT outcome and methadone dose requirements.

Gelernter J. Developmental perspective on the role of genes in smoking risk. (editorial). Biological Psychiatry 69(7): 616-617, 2011. (7 refs.)

Gillespie NA; Kendler KS; Neale MC. Psychometric modeling of cannabis initiation and use and the symptoms of cannabis abuse, dependence and withdrawal in a sample of male and female twins. Drug and Alcohol Dependence 118(2-3): 166-172, 2011. (79 refs.)

Background: Despite an emerging consensus that the DSM-IV diagnostic criteria for cannabis abuse and dependence are best represented by a single underlying liability, it remains unknown if latent class or hybrid models can better explain the data. Method: Using structured interviews, 7316 adult male and female twins provided complete data on DSM-IV symptoms of cannabis abuse and dependence. Our aim was to derive a parsimonious, best-fitting cannabis use disorder (CUD) phenotype based on DSM-III-R/IV criteria by comparing an array of psychometric models (latent factor analysis, latent class analysis and factor mixture modeling) using full information maximum likelihood ordinal data methods in Mx. Results: We found little evidence to support population heterogeneity since neither latent class nor hybrid factor mixture models provided a consistently good fit to the data. When conditioned on initiation and cannabis use, the endorsement patterns of the abuse, dependence and withdrawal criteria were best explained by two latent factors for males and females. The first was a general CUD factor for which genetic effects explained 53-54% of the variance. A less interpretable second factor included a mix of cross-loading dependence and withdrawal symptoms. Conclusions: This is the first study to compare competing measurement models to derive an empirically determined CUD phenotype. Commensurate with proposed changes to substance use disorders in the DSM-V, our results support an emerging consensus that a single CUD latent factor can more optimally assess the risk or liability underpinning correlated measures of use, abuse, dependence and withdrawal criterion.

Gizer IR; Ehlers CL; Vieten C; Seaton-Smith KL; Feiler HS; Lee JV et al. Linkage scan of nicotine dependence in the University of California, San Francisco (UCSF) Family Alcoholism Study. Psychological Medicine 41(4): 799-808, 2011. (54 refs.)

Background. Nicotine dependence has been shown to represent a heritable condition, and several research groups have performed linkage analysis to identify genomic regions influencing this disorder though only a limited number of the findings have been replicated. Method. In the present study, a genome-wide linkage scan for nicotine dependence was conducted in a community sample of 950 probands and 1204 relatives recruited through the University of California, San Francisco (UCSF) Family Alcoholism Study. A modified version of the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) with additional questions that probe nicotine use was used to derive DSM-IV nicotine dependence diagnoses. Results. A locus on chromosome 2q31.1 at 184 centiMorgans nearest to marker D2S2188 yielded a logarithm (base 10) of odds (LOD) score of 3.54 (point-wise empirical p = 0.000012). Additional peaks of interest were identified on chromosomes 2q13, 4p15.33-31, 11q25 and 12p11.23-21. Follow-up analyses were conducted examining the contributions of individual nicotine dependence symptoms to the chromosome 2q31.1 linkage peak as well as examining the relationship of this chromosomal region to alcohol dependence. Conclusions. The present report suggests that chromosome 2q31.1 confers risk to the development of nicotine dependence and that this region influences a broad range of nicotine dependence symptoms rather than a specific facet of the disorder. Further, the results show that this region is not linked to alcohol dependence in this population, and thus may influence nicotine dependence specifically.

Haberstick BC; Ehringer MA; Lessem JM; Hopfer CJ; Hewitt JK. Dizziness and the genetic influences on subjective experiences to initial cigarette use. Addiction 106(2): 391-399, 2011. (59 refs.)

Aim: To examine individual differences in positive and negative subjective experiences to initial cigarette use. Design: Retrospective self-reports of initial subjective experiences were examined to estimate the genetic and environmental influences and the extent of their covariation across different effects. Participants: Data was drawn from 2482 young adult same-and opposite sex twins- and siblings participating in the National Longitudinal Study of Adolescent Health. Measurement: Subjective experiences were retrospectively collected using the Early Smoking Experience (ESE) questionnaire. Findings: Positive experiences evidenced moderate heritable contributions (40%, 95% CI: 0.22 to 0.56), as did an overall hedonic measure (34%, 95% CI: 0.22 to 0.46) and dizziness (34%, 95% CI: 0.15 to 0.52). Negative experiences evidenced small heritable contributions (13%, 95% CI: 0.00 to 0.36). Individual specific environmental influences were strong and accounted for the remaining proportion of observed variation in these experiences. Multivariate genetic modeling identified a moderately heritable underlying factor (37%, 95% CI: 0.22 to 0.52) that influenced the covariation of diverse subjective experiences and loaded most heavily on dizziness. Positive experiences also evidence residual genetic influences that were uncorrelated with other subjective experiences. Conclusions: How a person experiences their initial few cigarettes is due to both heritable contributions and environmental experiences unique to the person. The covariation of diverse subjective experiences appears to be due to a heritable latent sensitivity to the chemicals contained in an average cigarette and is best indexed by dizziness.

Haberstick BC; Zeiger JS; Corley RP; Hopfer CJ; Stallings MC; Rhee SH et al. Common and drug-specific genetic influences on subjective effects to alcohol, tobacco and marijuana use. Addiction 106(1): 215-224, 2011. (49 refs.)

Aim: To examine variation in positive and negative subjective effects to alcohol, tobacco and marijuana and covariation between these three drugs and each effect. Design: Retrospective self-reports of subjective effects were collected to estimate the genetic and environmental influences and the extent of their specificity across three drugs. Participants: Data were drawn from 1299 adolescent and young adult same- and opposite sex twin- and sibling-pairs participating in the Colorado Center for Antisocial Drug Dependence (CADD). Setting: A large, collaborative, longitudinal study of substance use and antisocial behavior in community and clinical adolescents. Measurement: Subjective effects were assessed using a 13-item questionnaire that included positive and negative responses to alcohol, tobacco and marijuana. Findings: Heritable influences contributed moderately (additive genetic effects 16-56%) to positive and negative subjective effects to all three drugs and did not differ for males and females. Genetic and environmental contributions to positive and negative subjective effects are largely non-overlapping for tobacco and marijuana. Multivariate genetic modeling indicated that subjective effects to alcohol, tobacco and marijuana share a common, heritable etiology and that drug-specific genetic influences were an important contributor to individual differences in drug response. Conclusions: Results from our genetic analyses suggest that subjective effects to these commonly used and misused drugs are heritable and that the genetic and environmental influences on effects to one drug also influence subjective effects to other drugs.

Hamidovic A; Kasberger JL; Young TR; Goodloe RJ; Redline S; Buxbaum SG et al. Genetic variability of smoking persistence in African-Americans. Cancer Prevention Research 4(5): 729- 734, 2011. (30 refs.)

To date, most genetic association analyses of smoking behaviors have been conducted in populations of European ancestry and many of these studies focused on the phenotype that measures smoking quantity, that is, cigarettes per day. Additional association studies in diverse populations with different linkage disequilibrium patterns and an alternate phenotype, such as total tobacco exposure which accounts for intermittent periods of smoking cessation within a larger smoking period as measured in large cardiovascular risk studies, can aid the search for variants relevant to smoking behavior. For these reasons, we undertook an association analysis by using a genotyping array that includes 2,100 genes to analyze smoking persistence in unrelated African American participants from the Atherosclerosis Risk in Communities study, A locus located approximately 4 kb downstream from the 3'-UTR of the brain-derived neurotrophic factor (BDNF) significantly influenced smoking persistence. In addition, independent variants rs12915366 and rs12914385 in the cluster of genes encoding nicotinic acetylcholine receptor subunits (CHRNA5-CHRNA3-CHRNB4) on 15q25.1 were also associated with the phenotype in this sample of African American subjects. To our knowledge, this is the first study to more extensively evaluate the genome in the African American population, as a limited number of previous studies of smoking behavior in this population included evaluations of only single genomic regions.

Han SZ; Yang BZ; Kranzler HR; Oslin D; Anton R; Gelernter J. Association of CHRNA4 polymorphisms with smoking behavior in two populations. American Journal of Medical Genetics. Part B: Neuropsychiatric Genetics 156B(4): 421- 429, 2011. (45 refs.)

CHRNA4, the gene that encodes the nicotinic acetylcholine receptor alpha(4) subunit, is a potential candidate gene for nicotine dependence (ND). However, studies of the association of CHNRA4 with smoking behavior have shown inconsistent results. Our meta-analysis of linkage studies of smoking behavior identified a genome-wide significant linkage of the phenotype maximum number of cigarettes smoked in a 24-hour period to a region (20q13.12-q13.32) harboring CHRNA4. This motivated us to examine the association of CHRNA4 with smoking behavior in two independent samples. In this study, we examined five single nucleotide polymorphisms (SNPs) within CHRNA4 and three smoking-related behaviors: one quantitative trait [cigarettes smoked per day (CPD)], and two binary traits [DSM-IV diagnosis of ND and dichotomized Fagerstrom test of ND (FTND)], in 1,249 unrelated European-Americans (EAs) and 1,790 unrelated African-Americans (AAs). Using the combined sample with sex, age, and race as covariates, the synonymous SNP rs1044394 was significantly associated with ND (P = 0.001) and FTND (P = 0.01). Rs2236196, which has a low correlation with rs1044394, was also significantly associated with CPD (P = 0.003). The pattern of association for these SNPs was similar in AAs and EAs. After correction for multiple testing, the association between rs1044394 and ND in the combined sample remained significant (P = 0.033). In summary, our study supports association between CHRNA4 common variation and ND in AA and EA samples. Additional studies will be necessary to evaluate the role of rare variants at CHRNA4 for ND.

Handley ED; Chassin L; Haller MM; Bountress KE; Dandreaux D; Beltran I. Do executive and reactive disinhibition mediate the effects of familial substance use disorders on adolescent externalizing outcomes? Journal of Abnormal Psychology 120(3): 528-542, 2011. (104 refs.)

The present study examined the potential mediating roles of executive and reactive disinhibition in predicting conduct problems, attention-deficit/hyperactivity disorder (ADHD) symptoms, and substance use among adolescents with and without a family history of substance use disorders. Using data from 247 high-risk adolescents, parents, and grandparents, structural equation modeling indicated that reactive disinhibition, as measured by sensation seeking, mediated the effect of familial drug use disorders on all facets of the adolescent externalizing spectrum. Executive disinhibition, as measured by response disinhibition. spatial short term memory, and "trait" impulsivity, was associated with ADHD symptoms. Moreover, although executive functioning weakness were unrelated to familial substance use disorders, adolescents with familial alcohol use disorders were at risk for "trait" impulsivity marked by a lack of planning. These results illustrate the importance of "unpacking" the broad temperament style of disinhibition and of studying the processes that underlie the commonality among facets of the externalizing spectrum and processes that predict specific externalizing outcomes.

Hartz SM; Johnson EO; Saccone NL; Hatsukami D; Breslau N; Bierut LJ. Inclusion of African Americans in genetic studies: What is the barrier? American Journal of Epidemiology 174(3): 336-344, 2011. (25 refs.)

To facilitate an increase in the amount of data on minority subjects collected for genetic databases, the authors attempted to clarify barriers to African-American participation in genetic studies. They randomly sampled 78,072 subjects from the community (Missouri Family Registry, 2002-2007). Of these, 28,658 participated in a telephone screening interview, 3,179 were eligible to participate in the genetic study, and 1,919 participated in the genetic study. Response rates were examined in relation to the proportion of subjects in the area who were African-American according to US Census 2000 zip code demographic data. Compared with zip codes with fewer than 5% African Americans (average = 2% African-American), zip codes with at least 60% African Americans (average 87% African-American) had higher proportions of subjects with an incorrect address or telephone number but lower proportions of subjects who did not answer the telephone and subjects who refused the telephone interview (P < 0.0001). Based on reported race from the telephone screening, 71% of eligible African Americans and 57% of eligible European Americans participated in the genetic study (P < 0.0001). The results of this study suggest that increasing the number of African Americans in genetic databases may be achieved by increasing efforts to locate and contact them.

Heilig M; Goldman D; Berrettini W; O'Brien CP. Pharmacogenetic approaches to the treatment of alcohol addiction. Nature Reviews. Neuroscience 12(11): 670-684, 2011

Addictive disorders are partly heritable, chronic, relapsing conditions that account for a tremendous disease burden. Currently available addiction pharmacotherapies are only moderately successful, continue to be viewed with considerable scepticism outside the scientific community and have not become widely adopted as treatments. More effective medical treatments are needed to transform addiction treatment and address currently unmet medical needs. Emerging evidence from alcoholism research suggests that no single advance can be expected to fundamentally change treatment outcomes. Rather, studies of opioid, corticotropin-releasing factor, GABA and serotonin systems suggest that incremental advances in treatment outcomes will result from an improved understanding of the genetic heterogeneity among patients with alcohol addiction, and the development of personalized treatments.

Hendershot CS; Bryan AD; Ewing SWF; Claus ED; Hutchison KE. Preliminary evidence for associations of CHRM2 with substance use and disinhibition in adolescence. Journal of Abnormal Child Psychology 39(5): 671-681, 2011. (70 refs.)

Evidence for shared heritable influences across domains of substance use suggests that some genetic variants influence broad risk for externalizing behaviors. Theories of externalizing psychopathology also suggest that genetic liability for substance use manifests as temperamental risk factors, particularly those related to behavioral disinhibition, during adolescence. The cholinergic muscarinic receptor 2 gene (CHRM2) is a promising candidate for studying genetic influences on broad-based risk for externalizing traits. This study examined a candidate CHRM2 polymorphism (rs1455858) in relation to substance use and personality measures of disinhibition in a sample of high-risk adolescents (n = 124). Bivariate analyses and structural equation modeling (SEM) evaluated associations of rs1455858 with measures of drug involvement (alcohol, tobacco and marijuana) and disinhibition (indexed by impulsivity and sensation seeking scores). Bivariate analyses showed significant associations of CHRM2 with several behavioral phenotypes. In SEM analyses CHRM2 related significantly to latent measures of substance use and disinhibition; additionally, disinhibition mediated the association of CHRM2 with substance use. These results suggest that CHRM2 variants are potentially relevant for adolescent substance use and that temperamental risk factors could contribute to these associations.

Hendershot CS; Witkiewitz K; George WH; Marlatt GA. Relapse prevention for addictive behaviors. (review). Substance Abuse Treatment, Prevention and Policy 6: e-article 17, 2011. (140 refs.)

The Relapse Prevention (RP) model has been a mainstay of addictions theory and treatment since its introduction three decades ago. This paper provides an overview and update of RP for addictive behaviors with a focus on developments over the last decade (2000-2010). Major treatment outcome studies and meta-analyses are summarized, as are selected empirical findings relevant to the tenets of the RP model. Notable advances in RP in the last decade include the introduction of a reformulated cognitive-behavioral model of relapse, the application of advanced statistical methods to model relapse in large randomized trials, and the development of mindfulness-based relapse prevention. We also review the emergent literature on genetic correlates of relapse following pharmacological and behavioral treatments. The continued influence of RP is evidenced by its integration in most cognitive-behavioral substance use interventions. However, the tendency to subsume RP within other treatment modalities has posed a barrier to systematic evaluation of the RP model. Overall, RP remains an influential cognitive-behavioral framework that can inform both theoretical and clinical approaches to understanding and facilitating behavior change.

Hicks BM; Schalet BD; Malone SM; Iacono WG; McGue M. Psychometric and genetic architecture of substance use disorder and behavioral disinhibition measures for gene association studies. Behavior Genetics 41(4): 459-475, 2011. (85 refs.)

Using large twin, family, and adoption studies conducted at the Minnesota Center for Twin and Family Research, we describe our efforts to develop measures of substance use disorder (SUD) related phenotypes for targets in genome wide association analyses. Beginning with a diverse set of relatively narrow facet-level measures, we identified 5 constructs of intermediate complexity: nicotine, alcohol consumption, alcohol dependence, illicit drug, and behavioral disinhibition. The 5 constructs were moderately correlated (mean r = .57) reflecting a general externalizing liability to substance abuse and antisocial behavior. Analyses of the twin and adoption data revealed that this general externalizing liability accounted for much of the genetic risk in each of the intermediate-level constructs, though each also exhibited significant unique genetic and environmental risk. Additional analyses revealed substantial effects for age and sex, significant shared environmental effects, and that the mechanism of these shared environmental effects operates via siblings rather than parents. Our results provide a foundation for genome wide association analyses to detect risk alleles for SUDs as well as novel insights into genetic and environmental risk for SUDs.

Hong LE; Yang X; Wonodi I; Hodgkinson CA; Goldman D; Stine OC et al. A CHRNA5 allele related to nicotine addiction and schizophrenia. Genes, Brain and Behavior 10(5): 530-535, 2011. (43 refs.)

Schizophrenia and nicotine addiction are both highly heritable phenotypes. Because individuals with schizophrenia have a higher rate of smoking than those in the general population, one could hypothesize that genes associated with smoking might be overrepresented in schizophrenia and thus help explain their increased smoking incidence. Although a number of genes have been proposed to explain the increased smoking risk in schizophrenia, none of them have been consistently linked to smoking and schizophrenia, and thus difficult to explain the increased smoking in schizophrenia. A functional smoking-related nicotinic acetylcholine receptor alpha 5 subunit gene (CHRNA5) nonsynonymous single nucleotide polymorphism (SNP) rs16969968 (Asp398Asn) has recently been discovered and replicated. As such, we tested whether this variant contributes to smoking in schizophrenia in a sample of 313 schizophrenia patients and 525 controls. The Asp398Asn risk allele is significantly associated with smoking severity independently in schizophrenia patient smokers (P = 0.001) and control smokers (P = 0.029). Furthermore, the same risk allele is significantly associated with schizophrenia in both Caucasian (P = 0.022) and African-American (P = 0.006) nonsmoker schizophrenia patients compared with control nonsmokers. Intriguingly, this SNP was not significantly associated with smoking status (smokers vs. nonsmokers) in either schizophrenia patients or controls. Therefore, our study identifies a genetic variant that is simultaneously linked to smoking and schizophrenia in the same cohort, but whether this SNP contributes to the increased smoking prevalence in schizophrenia patients requires additional studies.

Hsieh CH; Chang JWC; Hsieh JJ; Hsu T; Huang SF; Liao CT et al. Epidermal growth factor receptor mutations in patients with oral cavity cancer in a betel nut chewing-prevalent area. Head and Neck 33(12): 1758-1764, 2011. (34 refs.)

Background. Epidermal growth factor receptor (EGFR) mutations exist in patients with oral cavity squamous cell carcinoma (OSCC), but few data about mutation patterns with clinical outcomes were reported. Methods. Fifty-six formalin-fixed paraffin-embedded tumor samples were obtained surgically from OSCC patients. Direct sequencing of EGFR was carried out using nested polymerase chain reaction. The relationship between EGFR status and clinical courses was analyzed. Results. Two (3.56%) missense mutations (G857R; L862Q) in exon 20 were identified. Two types of silent mutation, A859A in exon 21 (1.79%) and Q787Q mutations in exon 20 (30.36%), were also found. No mutation was detected in exons 18 and 19. No significant difference in disease-free survival and locoregional control rate was shown between patients with and without Q787Q mutation. Conclusions. We identified a high frequency of Q787Q mutation and a less prevalent active EGFR mutation in OSCC patients in Taiwan where betel nut is commonly chewed.

Hutchison KE; Ray LA. New approaches to identifying rare genetic variants associated with nicotine dependence. (editorial). Biological Psychiatry 70(6): 500-501, 2011. (8 refs.)

Iacono WG; Malone SM. Developmental endophenotypes: Indexing genetic risk for substance abuse with the p300 brain event-related potential. Child Development Perspectives 5(4): 239-247, 2011. (72 refs.)

Although substance use disorders (SUDs) are heritable, their complexity has made identifying genes underlying their development challenging. Endophenotypes, biologically informed quantitative measures that index genetic risk for a disorder, are being recognized for their potential to assist the search for disorder-relevant genes. After outlining criteria for an endophenotype that includes developmental considerations, this article reviews how the brain P300 response serves as an index of genetic risk for substance abuse and related externalizing disorders. The P300 response is highly heritable and associated broadly with characteristics of externalizing disorder, including childhood disruptive disorders, antisociality, and precocious expression of deviant behavior. This association appears to be mediated by shared genetic influences. Prospective studies confirm that reduced P300 amplitude present in youth prior to significant exposure to addictive substances is associated with the subsequent development of SUDs. Despite pronounced change in mean level over the course of development, P300 amplitude shows strong rank-order stability with repeated assessment through young adulthood. In addition, P300 developmental trajectories based on multiple assessments show very high heritability and may be especially informative as measures of genetic risk. Collectively, these findings provide strong support for the idea that P300 amplitude and its change through development reflect genetic vulnerability to substance abuse and related externalizing psychopathology.

Ishii T; Wakabayashi R; Kurosaki H; Gemma A; Kida K. Association of serotonin transporter gene variation with smoking, chronic obstructive pulmonary disease, and its depressive symptoms. Journal of Human Genetics 56(1): 41-46, 2011. (39 refs.)

A serotonin transporter gene, SLC6A4, is thought to be related to nicotine dependence and depression, one of the comorbidities of chronic obstructive pulmonary disease (COPD). To investigate the association between SLC6A4 variation and tobacco consumption, susceptibility to COPD, and depression status. In all, 247 patients with COPD and 119 control subjects were genotyped for 5 tag single-nucleotide polymorphisms (SNPs) of SLC6A4. We analyzed the correlation between these genotypes and COPD, using the results of a pulmonary function test or chest computed tomography; data on tobacco consumption (pack-years); and the depression score based on the hospital anxiety and depression scale (HADS) after adjusting for age, gender, and smoking status (and pack-years, when appropriate). The rare allele rs2020936 was significantly associated with COPD incidence in the trend model (P = 0.003; odds ratio, 2.20; 95% confidence interval, 1.31-3.74). This allele was also associated with the number of pack-years (P = 0.026). The major allele of another SNP of SLC6A4, namely rs3794808, correlated with the HADS depression score (P = 0.016). We conclude that SLC6A4 variation affects COPD pathogenesis, and this effect depends partly on tobacco consumption. SLC6A4 variation also affects depressive symptoms. SLC6A4 could be modified to prevent COPD and treat the depressive symptoms of COPD.

Jafari N; Hintzen RQ. The association between cigarette smoking and multiple sclerosis. Journal of the Neurological Sciences 311(1-2, special issue): 78-85, 2011. (94 refs.)

Genetic factors partially explain the susceptibility of multiple sclerosis (MS) and might even relate to the clinical course. Still, many epidemiological studies point at an important role for environmental factors in MS. Smoking is one of the major candidates. In this review we provide an overview of the epidemiological studies on cigarette smoking and the association on MS risk and MS clinical course. In addition, we discuss the possible biological pathways that may influence neurological damage in MS. Moreover, the relation of smoking with other environmental MS risk factors will be addressed.

Ji XM; Zhang WD; Xie CH; Wang BC; Zhang G; Zhou FX. Nasopharyngeal carcinoma risk by histologic type in central China: impact of smoking, alcohol and family history. International Journal of Cancer 129(3): 724-732, 2011. (43 refs.)

The role of cigarette smoking, alcohol use, family history of cancer and the interaction of cigarettes and family history in the etiology of Nasopharyngeal carcinoma (NPC) in general and within each histologic type are unclear. We conducted a case-control study among 1,044 Han Chinese patients with NPC and 1,095 Han Chinese cancer-free control subjects. Logistic regression was used to analyze the association between histologic type of NPC and cigarette smoking, alcohol drinking and family history. The results indicated that NPC was significantly associated with cigarette smoking [adjusted odds ratio (OR) = 2.97, 95% confidence interval (CI), 2.38-3.70], and the association exhibited a dose-response relationship for intensity, duration, and cumulative consumption of cigarettes (p(trend) < 0.0001 for intensity, duration and cumulative consumption of cigarettes). Positive family history of cancer led to a significant 12-fold elevated risk of NPC (adjusted OR = 12.95, 95% CI, 7.12-23.54) and acted jointly with cigarettes in contributing to NPC risk (adjusted OR = 56.68, 95% CI, 17.25-186.19). The association of NPC risk with cigarettes was stronger for nonkeratinizing carcinoma than for keratinizing squamous cell carcinoma (KSCC), whereas family history was more closely associated with KSCC. NPC risk was not associated with alcohol consumption. Our study demonstrated that cigarette smoking and family history of cancer could serve independently and jointly as risk factors for etiology of NPC and might affect the risk of histology-specific NPC differently. This knowledge may help facilitate comprehension of NPC etiology in general as well as within each histologic type, and thereby improve prevention efforts.

Kahn RS; Linszen DH; van Os J; Wiersma D; Bruggeman R; Cahn W et al. Evidence that familial liability for psychosis is expressed as differential sensitivity to cannabis an analysis of patient-sibling and sibling-control pairs. Archives of General Psychiatry 68(2): 138-147, 2011. (61 refs.)

Context: Individual differences in cannabis sensitivity may be associated with genetic risk for psychotic disorder. Objectives: To demonstrate and replicate, using 2 conceptually different genetic epidemiological designs, that (familial) liability to psychosis is associated with sensitivity to cannabis. Design, Setting, and Participants: Sibling-control and cross-sibling comparisons using samples of patients with a psychotic disorder (n=1120), their siblings (n=1057), and community controls (n=590) in the Netherlands and Flanders. Main Outcome Measures: Positive and negative schizotypy using the Structured Interview for Schizotypy-Revised (for siblings and controls) and self-reported positive and negative psychotic experiences using the Community Assessment of Psychic Experiences (for siblings and patients). Cannabis use was assessed as current use (by urinalysis) and lifetime frequency of use (by Composite International Diagnostic Interview). Results: In the sibling-control comparison, siblings displayed more than 15 times greater sensitivity to positive schizotypy associated with particularly current cannabis use by urinalysis (adjusted B=0.197, P<.001) than controls (adjusted B=0.013, P=.86) (P interaction=.04) and a similar difference in sensitivity to its effect on negative schizotypy (siblings: adjusted B=0.120, P<.001; controls: B=-0.008, P=.87; P interaction=.03). Similarly, siblings exposed to cannabis resembled their patient relative nearly 10 times more closely in the positive psychotic dimension of the Community Assessment of Psychic Experiences (adjusted B=0.278, P<.001) compared with nonexposed siblings (adjusted B=0.025, P=.12) (P interaction<.001). No significant effect was apparent for the Community Assessment of Psychic Experiences negative domain, although the association was directionally similar (2 times more resemblance; P interaction=.17). Crosssibling, cross-trait analyses suggested that the mechanism underlying these findings was moderation (familial risk increasing sensitivity to cannabis) rather than mediation (familial risk increasing use of cannabis). Conclusions: Genetic risk for psychotic disorder may be expressed in part as sensitivity to the psychotomimetic effect of cannabis. Cannabis use may synergistically combine with preexisting psychosis liability to cause positive and negative symptoms of psychosis.

Kavanagh DJ. Commentary on Liang et al. (2011): Unravelling the tangle of comorbidity - are we there yet? (commentary). Addiction 106(6): 1135- 1136, 2011. (13 refs.)

Kenny PJ. Reward mechanisms in obesity: New insights and future directions. (review). Neuron 69(4): 664-679, 2011. (204 refs.)

Food is consumed in order to maintain energy balance at homeostatic levels. In addition, palatable food is also consumed for its hedonic properties independent of energy status. Such reward-related consumption can result in caloric intake exceeding requirements and is considered a major culprit in the rapidly increasing rates of obesity in developed countries. Compared with homeostatic mechanisms of feeding, much less is known about how hedonic systems in brain influence food intake. Intriguingly, excessive consumption of palatable food can trigger neuroadaptive responses in brain reward circuitries similar to drugs of abuse. Furthermore, similar genetic vulnerabilities in brain reward systems can increase predisposition to drug addiction and obesity. Here, recent advances in our understanding of the brain circuitries that regulate hedonic aspects of feeding behavior will be reviewed. Also, emerging evidence suggesting that obesity and drug addiction may share common hedonic mechanisms will also be considered.

Keskitalo-Vuokko K; Pitkaniemi J; Broms U; Heliovaara M; Aromaa A; Perola M et al. Associations of nicotine intake measures with CHRN genes in Finnish smokers. Nicotine & Tobacco Research 13(8): 686-690, 2011. (25 refs.)

Introduction: Genetic effects contribute to individual differences in smoking behavior. Persistence to smoke despite known harmful health effects is mostly driven by nicotine addiction. As the physiological effects of nicotine are mediated by nicotinic acetylcholine receptors (nAChRs), we aimed at examining whether single nucleotide polymorphisms (SNPs) residing in nAChR subunit (CHRN) genes, other than CHRNA3/CHRNA5/ CHRNB4 gene cluster previously showing association in our sample, are associated with smoking quantity or serum cotinine levels. Methods: The study sample consisted of 485 Finnish adult daily smokers (age 30-75 years, 59% men) assessed for the number of cigarettes smoked per day (CPD) and serum cotinine level. We first studied SNPs residing on selected nAChR subunit genes (CHRNA2, CHRNA4, CHRNA6/CHRNB3, CHRNA7, CHRNA9, CHRNA10, CHRNB2, CHRNG/CHRND) genotyped within a genome-wide association study for single SNP and multiple SNP associations by ordinal regression. Next, we explored individual haplotype associations using sliding window technique. Results: At one of the 8 loci studied, CHRNG/CHRND (chr2), single SNP (rs1190452), multiple SNP, and 2-SNP haplotype analyses (SNPs rs4973539-rs1190452) all showed statistically significant association with cotinine level. The median cotinine levels varied between the 2-SNP haplotypes from 220 ng/ml (AA haplotype) to 249 ng/ml (AG haplotype). We did not observe significant associations with CPD. Conclusions: These results provide further evidence that the g-d nAChR subunit gene region is associated with cotinine levels but not with the number of CPD, illustrating the usefulness of biomarkers in genetic analyses.

Kishi T; Fukuo Y; Okochi T; Kitajima T; Ujike H; Inada T. No significant association between SIRT1 gene and methamphetamine-induced psychosis in the Japanese population. Human Psychopharmacology: Clinical and Experimental 26(7): 445-450, 2011. (36 refs.)

Objectives We previously showed that the sirtuin 1 gene (SIRT1 gene), one of the clock genes, was associated with schizophrenia in a Japanese patient population. Because the symptoms of methamphetamine (METH)-induced psychosis are similar to those of paranoid type schizophrenia and because not every METH user develops psychosis, it is conceivable that METH-induced psychosis and schizophrenia have common susceptibility genes. Therefore, we conducted an analysis of the association of SIRT1 gene with METH-induced psychosis, hypothesizing a significant relationship. Methods This paper presents a case-control study of the SIRT1 gene in 515 Japanese individuals (197 with METH-induced psychosis and 318 age-matched and sex-matched controls) with four tagging single nucleotide polymorphisms (rs12778366, rs2273773, rs4746720, and rs10997875), selected a priori using the HapMap database. Results rs10997875 (located in the 3' flanking region) was associated with METH-induced psychosis (unadjusted p(genotype)=0.0203). However, these results became non-significant after Bonferroni correction (corrected p(genotype)=0.0812). In the all-marker haplotype analysis, the SIRT1 gene was not associated with METH-induced psychosis (p=0.146). Conclusion Our findings suggest that SIRT1 gene does not contribute to the development of METH-induced psychosis in the Japanese population. However, a replication study using larger samples should be conducted to obtain conclusive results.

Kishi T; Okochi T; Kitajima T; Ujike H; Inada T; Yamada M et al. Lack of association between translin-associated factor X gene (TSNAX) and methamphetamine dependence in the Japanese population. (review). Progress in Neuro-Psychopharmacology & Biological Psychiatry 35(7): 1618-1622, 2011. (30 refs.)

Objectives: Recently, we detected that the prokineticin 2 receptor gene was associated with not only major depressive disorder (MDD) but also methamphetamine dependence. Therefore, it is possible that mood disorders and drug addiction have shared susceptibility genes. The translin-associated factor X gene (TSNAX)/disrupted-in-schizophrenia-1 gene (DISC1) has been associated with psychiatric disorders, including schizophrenia, MDD and bipolar disorder. TSNAX is located immediately upstream of DISC1 and has been shown to undergo intergenic splicing with DISC1. Based on this evidence, we hypothesized that TSNAX might be a good candidate gene for methamphetamine dependence. Methods: We conducted a case-control study of Japanese individuals (215 with methamphetamine dependence and 318 age- and sex-matched controls) with three tagging SNPs (rs1630250, rs766288 and rs6662926) selected by HapMap database. Results: rs1630250 was associated in males with methamphetamine dependence in the allele analysis (P-value: 0.0253). However, these results did not remain significant after Bonferroni correction to adjust for multiple comparisons (corrected P-value: 0.152). Conclusion: Our findings suggest that TSNAX does not play a role in methamphetamine dependence in the Japanese population. A replication study using larger samples needs to be conducted to obtain conclusive results.

Koh WP; Nelson HH; Yuan JM; Van den Berg D; Jin AZ; Wang RW et al. Glutathione S-transferase (GST) gene polymorphisms, cigarette smoking and colorectal cancer risk among Chinese in Singapore. Carcinogenesis 32(10): 1507-1511, 2011. (37 refs.)

Cigarette smoking is a risk factor for colorectal cancer. Putative colorectal procarcinogens in tobacco smoke include polycyclic aromatic hydrocarbons and heterocyclic aromatic amines that are known substrates of glutathione S-transferases (GSTs). This study examined the influence of functional GST gene polymorphisms on the smoking-colorectal cancer association in a population known to be minimally exposed to dietary sources of these procarcinogens. Incident cases of colorectal cancer (n = 480) and matched controls (n = 1167) were selected from the Singapore Chinese Health Study, a population-based prospective cohort of 63 257 men and women who have been followed since 1993. We determined the deletion polymorphisms of GSTM1 and GSTT1 and the functional polymorphism at codon 105 of GSTP1 for each subject. A three level composite GST index was used to examine if GST profile affected a smoker's risk of developing colorectal cancer. While there was no statistically significant association between cigarette smoking and colorectal cancer risk among subjects absent of any at-risk GST genotypes, smokers possessing two to three at-risk GST genotypes exhibited a statistically significant increased risk of colorectal cancer compared with non-smokers (P = 0.0002). In this latter stratum, heavy smokers exhibited a > 5-fold increased risk relative to never-smokers (odds ratio, 5.43; 95% confidence interval, 2.22-13.23). Subjects with one at-risk GST genotype displayed a statistically significant but weaker association with smoking. These findings suggest that GST gene polymorphisms influence interindividual susceptibility to smoking-associated colorectal cancer. Our data indicate an important role for GST enzymes in the detoxification of colorectal carcinogens in tobacco smoke.

Koskenvuo K; Broms U; Korhonen T; Laitinen LA; Huunan-Seppala A; Keistinen T et al. Smoking strongly predicts disability retirement due to COPD: the Finnish Twin Cohort Study. European Respiratory Journal 37(1): 26-31, 2011. (34 refs.)

No previous studies on the association of smoking behaviour with disability retirement due to register verified chronic obstructive pulmonary disease (COPD) exist. This 30-yr follow-up study examined how strongly aspects of cigarette smoking predict disability retirement due to COPD. The study population consisted of 24,043 adult Finnish twins (49.7% females) followed from 1975 to 2004. At baseline the participants had responded to a questionnaire. Information on retirement was obtained from the Finnish pension registers. Smoking strongly predicted disability retirement due to COPD. In comparison to never-smokers, age adjusted hazard ratio (HR) for current smokers was 22.0 (95% CI 10.0-48.5) and for smokers with >= 12 pack-yrs was 27.3 (95% CI 12.6-59.5). Similar estimates of risk were observed in within-pair analyses of twin pairs discordant for disability retirement due to COPD. Among discordant monozygotic pairs those with disability pension due to COPD were more often current smokers. The effect of early smoking onset (<18 yrs) on the risk of disability retirement due to COPD remained after adjustment for the amount smoked (HR 1.70, 95% CI 1.08-2.68). Smoking strongly predicts disability retirement due to COPD. Preventive measures against disability retirement and other harmful consequences of tobacco smoking should receive greater emphasis.

Lau C; Rogers JM; Desai M; Ross MG. Fetal programming of adult disease: Implications for prenatal care. Obstetrics and Gynecology 117(4): 978-985, 2011. (80 refs.)

The obesity epidemic, including a marked increase in the prevalence of obesity among pregnant women, represents a critical public health problem in the United States and throughout the world. Over the past two decades, it has been increasingly recognized that the risk of adult health disorders, particularly metabolic syndrome, can be markedly influenced by prenatal and infant environmental exposures (ie, developmental programming). Low birth weight, together with infant catch-up growth, is associated with a significant risk of adult obesity and cardiovascular disease, as well as adverse effects on pulmonary, renal, and cerebral function. Conversely, exposure to maternal obesity or high birth weight also represents an increased risk for childhood and adult obesity. In addition, fetal exposure to select chemicals (eg, phytoestrogens) or environmental pollutants (eg, tobacco smoke) may affect the predisposition to adult disease. Animal models have confirmed human epidemiologic findings and provided insight into putative programming mechanisms, including altered organ development, cellular signaling responses, and epigenetic modifications (ie, control of gene expression without modification of DNA sequence). Prenatal care is transitioning to incorporate goals of optimizing maternal, fetal, and neonatal health to prevent or reduce adult-onset diseases. Guidelines regarding optimal pregnancy nutrition and weight gain, management of low-and high-fetal-weight pregnancies, use of maternal glucocorticoids, and newborn feeding strategies, among others, have yet to fully integrate long-term consequences on adult health.

Lecarpentier J; Nogues C; Mouret-Fourme E; Stoppa-Lyonnet D; Lasset C; Caron O et al. Variation in breast cancer risk with mutation position, smoking, alcohol, and chest X-ray history, in the French National BRCA1/2 carrier cohort (GENEPSO). Breast Cancer Research and Treatment 130(3): 927-938, 2011. (40 refs.)

Germline mutations in BRCA1/2 confer a high risk of breast cancer (BC), but the magnitude of this risk varies according to various factors. Although controversial, there are data to support the hypothesis of allelic-risk heterogeneity. We assessed variation in BC risk according to the location of mutations recorded in the French study GENEPSO. Since the women in this study were selected from high-risk families, oversampling of affected women was eliminated by using a weighted Cox-regression model. Women were censored at the date of diagnosis when affected by any cancer, or the date of interview when unaffected. A total of 990 women were selected for the analysis: 379 were classified as affected, 611 as unaffected. For BRCA1, there was some evidence of a central region where the risk of BC is lower (codons 374-1161) (HR = 0.59, P = 0.04). For BRCA2, there was a strong evidence for a region at decreased risk (codons 957-1827) (HR = 0.35, P = 0.005) and for one at increased risk (codons 2546-2968) (HR = 3.56, P = 0.01). Moreover, we found an important association between radiation exposure from chest X-rays and BC risk (HR = 4.29, P < 10(-3)) and a positive association between smoking more than 21 pack-years and BC risk (HR = 2.09, P = 0.04). No significant variation in BC risk associated with chest X-ray exposure, smoking, and alcohol consumption was found according to the location of the mutation in BRCA1 and BRCA2. Our findings are consistent with those suggesting that the risk of BC is lower in the central regions of BRCA1/2. A new high-risk region in BRCA2 is described. Taking into account environmental and lifestyle modifiers, the location of mutations might be important in the clinical management of BRCA mutation carriers.

Li L; Zhu GQ; Meng T; Shi JY; Wu J; Xu X et al. Biological and epidemiological evidence of interaction of infant genotypes at Rs7205289 and maternal passive smoking in cleft palate. American Journal of Medical Genetics. Part A 155A(12): 2940-2948, 2011. (49 refs.)

The noncoding SNP rs7205289, located in the microRNA-140 gene has been associated with cleft palate risk. MiR-140 was found to regulate zebrafish palatal development in vivo and its expression level be reduced by environmental smoke exposure in vitro. Therefore, we sought to investigate whether the A allele of rs7205289 and maternal smoke exposure during the first trimester might contribute to cleft palate risk by regulating microRNA-140. We used in situ hybridization to explore the microRNA-140 expression pattern. A luciferase reporting system and Western blot were used to validate the target of microRNA-140. Mouse palatal mesenchymal cells (MPMC) were transfected with microRNA-140 expression vectors, or treated with cigarette smoke extract. In addition, we performed a hospital-based casecontrol study in 169 patients with nonsyndromic cleft palate and 306 unaffected controls. We demonstrated microRNA-140 expression in mouse palatal shelves from embryonic days 12 to 15. Pdgfra was the target of microRNA-140 in MPMC. When these cells were transfected with the minor allele vector or exposed to cigarette smoke extract, they showed a decrease in microRNA-140 expression. Epidemiological analyses showed that infants with CA/AA genotypes and exposed to maternal passive smoking during pregnancy had evidence of synergistic interaction in contributing to cleft palate risk. We concluded that infants with CA/AA genotypes at rs7205289 and maternal passive smoking during the first trimester may synergistically contribute to cleft palate risk by decreasing microRNA-140 during palatal development.

Li T; Yu SY; Du J; Chen HH; Jiang HF; Xu K et al. Role of novelty seeking personality traits as mediator of the association between COMT and onset age of drug use in Chinese heroin dependent patients. PLoS ONE 6(8): e22923, 2011. (51 refs.)

Background: Personality traits such as novelty seeking (NS) are associated with substance dependence but the mechanism underlying this association remains uncertain. Previous studies have focused on the role of the dopamine pathway. Objective: Examine the relationships between allelic variants of the catechol-O-methlytransferase (COMT) gene, NS personality traits, and age of onset of drug use in heroin-dependent subjects in China. Methods: The 478 heroin dependent subjects from four drug rehabilitation centers in Shanghai who were genotyped for eight tagging single nucleotide polymorphisms (SNP) on the COMT gene completed the NS subscale from the Temperament and Character Inventory. Multivaritate analyses were used to assess the potential mediating role of NS personality traits in the association between COMT gene variants and the age of onset of heroin use. Principal Findings and Conclusions: In the univariate analysis the COMT rs737866 gene variants were independently associated with both NS and age of onset of drug use: those with the TT genotype had higher NS subscale scores and an earlier onset age of heroin use than individuals with CT or CC genotypes. In the multivariate analysis the inclusion of the NS subscore variable weakened the relationship between the COMT rs737866 TT genotype and an earlier age of onset of drug use. Our findings that COMT is associated with both NS personality traits and with the age of onset of heroin use helps to clarify the complex relationship between genetic and psychological factors in the development of substance abuse.

Liang WB; Chikritzhs T; Lenton S. Affective disorders and anxiety disorders predict the risk of drug harmful use and dependence. Addiction 106(6): 1126-1134, 2011. (42 refs.)

Aim: To investigate whether affective disorders, anxiety disorders and alcohol use disorders may increase the risk of subsequently developing drug (non-alcohol-related) dependence and/or drug (non-alcohol-related) harmful use. Setting and design: A retrospective cohort study based on nationally representative household survey data collected from the 2007 National Survey of Mental Health and Wellbeing (MHW). Measurement: The MHW survey applied the World Mental Health Survey Initiative version of the Composite International Diagnostic Interview (WMH-CIDI 3.0) to collect information on ICD-10 mental disorder diagnoses. Ages at first onset for mental disorders and harmful drug use were used to reconstruct the cohort according to definition of exposure, time at risk and outcome. Participants: A total of 8841 Australian adults aged 18-85 years who were included in the 2007 MHW survey. Findings: Participants with affective disorders and anxiety disorders were at higher risk of drug harmful use and drug dependence, and the effects did not vary by the length of time respondents had been exposed to mental disorders. Conclusion: It is uncertain whether experience of affective disorders and anxiety disorders, possibly prior to the disorder being identified by the individual or a health worker, may lead to self-medication with psychoactive substances or whether common genetic factors linking mental disorder and drug use disorders are the underlying cause. Symptoms of mental health disorders should alert health-care providers to the possibility of drug use disorder comorbidity and the need for early intervention, especially among young males.

Lopez RVM; Zago MA; Eluf-Neto J; Curado MP; Daudt AW; da Silva WA et al. Education, tobacco smoking, alcohol consumption, and IL-2 and IL-6 gene polymorphisms in the survival of head and neck cancer. Brazilian Journal of Medical and Biological Research 44(10): 1006-1012, 2011. (40 refs.)

The association of education, tobacco smoking, alcohol consumption, and interleukin-2 (IL-2 +114 and -384) and -6 (IL-6 -174) DNA polymorphisms with head and neck squamous cell carcinoma (HNSCC) was investigated in a cohort study of 445 subjects. IL-2 and IL-6 genotypes were determined by real-time PCR. Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) of disease-specific survival according to anatomical sites of the head and neck. Mean age was 56 years and most patients were males (87.6%). Subjects with 5 or more years of schooling had better survival in larynx cancer. Smoking had no effect on HNSCC survival, but alcohol consumption had a statistically significant effect on larynx cancer. IL-2 gene +114 G/T (HR = 0.52; 95% CI = 0.15-1.81) and T/T (HR = 0.22; 95% CI = 0.02-3.19) genotypes were associated with better survival in hypopharynx cancer. IL-2 + 114 G/T was a predictor of poor survival in oral cavity/oropharynx cancer and larynx cancer (HR = 1.32; 95% CI = 0.61-2.85). IL-2 -384 G/T was associated with better survival in oral cavity/oropharynx cancer (HR = 0.80; 95% CI = 0.45-1.42) and hypopharynx cancer (HR = 0.68; 95% CI = 0.21-2.20), but an inverse relationship was observed for larynx cancer. IL-6 -174 G/C was associated with better survival in hypopharynx cancer (HR = 0.68; 95% CI = 0.26-1.78) and larynx cancer (HR = 0.93; 95% CI = 0.42-2.07), and C/C reduced mortality in larynx cancer. In general, our results are similar to previous reports on the value of education, smoking, alcohol consumption, and IL-2 and IL-6 genetic polymorphisms for the prognosis of HNSCC, but the risks due to these variables are small and estimates imprecise.

Loth E; Carvalho F; Schumann G. The contribution of imaging genetics to the development of predictive markers for addictions. (review). Trends in Cognitive Sciences 15(9, special issue): 436-446, 2011. (101 refs.)

A key challenge for intervention and prevention of addictions is the identification of genetic, neurobiological and cognitive risk profiles that can predict which adolescents are at risk for addiction. Abnormalities in reinforcement behaviour have been linked to addiction vulnerability and imaging genetic studies have begun to elucidate the mechanisms by which genetic and environmental factors influence brain function underlying individual variability in reinforcement behaviour. Most studies have examined associations between a few well-characterised candidate polymorphisms and task-related brain activation differences in individual regions of interest. Here we propose that integrating the imaging genetic strategy with biological network approaches and longitudinal adolescent designs in large multi-centre samples may offer promising opportunities to identify risk markers for early diagnosis, progression and prediction of addictions.

Maes HH; Neale MC; Chen XN; Chen JC; Prescott CA; Kendler KS. A twin association study of nicotine dependence with markers in the CHRNA3 and CHRNA5 genes. Behavior Genetics 41(5): 680-690, 2011. (29 refs.)

Twin and family studies have provided overwhelming evidence for the genetic basis of individual differences in tobacco initiation (TI), regular smoking (RS) and nicotine dependence (ND). However, only a few genes have been reliably associated with ND. We used a finite mixture distribution model to examine the significance and effect size of the association of previously identified and replicated specific variants in the CHRNA5 and CHRNA3 receptor genes with ND, against the background of genetic and environmental risk factors for ND. We hypothesize that additional phenotypic information in relatives who have not been genotyped can be used to increase the power of detecting the genetic variant. The nicotine measures were assessed by personal interview in female, male and opposite sex twin pairs (N = 4,153) from the population-based Virginia Twin Registry. Three SNPs in the CHRNA5 and CHRNA3 receptor genes, previously shown to be significantly associated with ND in this sample, were replicated in the augmented analyses; they accounted for less than one percent of the genetic variance in liability to ND, which is estimated to be over 50% of the phenotypic variance. The significance of these effects was increased by adding twins with phenotype but without genotype data, but gains are limited and variable. The SNPs associated with ND did not show a significant association with either TI or RS and appear to be specific to the addictive stage of ND, characterized by current smoking and smoking a large amount of cigarettes per day. Furthermore, these SNPs did not appear to be associated with the remaining items comprising the FTND scale. This study confirmed a significant contribution of the CHRNA receptor on different forms of tobacco dependence. However, the genetic variant only accounted for little of the total genetic variance for liability to ND. Including phenotypic data on ungenotyped relatives can improve the statistical power to detect the effects of genetic variants when they contribute to individual differences in the phenotype.

Malison RT; Kalayasiri R; Sanichwankul K; Sughondhabirom A; Mutirangura A; Pittman B et al. Inter-rater reliability and concurrent validity of DSM-IV opioid dependence in a Hmong isolate using the Thai version of the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA). Addictive Behaviors 36(1-2): 156-160, 2011. (14 refs.)

Because Isolated populations offer relative genetic and environmental homogeneity they are important resources for mapping genes for complex traits. Reliable and valid phenotypic characterization of the disease in the population studied is essential. We examined diagnostic reliability and concurrent validity of DSM IV opioid dependence (OD) in a Hmong population in Thailand with historically high rates of opium (and heroin) use 578 Thai speaking Hmong individuals were assessed for lifetime OD using Thai versions of both the Semi Structured Assessment for Drug Dependence and Alcoholism (Thai SSADDA) and the Mini Neuropsychiatric Interview (Thai MINI adapted for lifetime diagnoses). In a subsample of 123 individuals two raters interviewed each subject independently within a 2 week period Chance-corrected agreement on the OD diagnosis was assessed between raters and instruments Results showed excellent agreement for the DSM IV diagnosis of OD both for the SSADDA (kappa=0 97) and MINI (kappa=1 00) and between the SSADDA and MINI (kappa=0 97). Consistent with reliability assessments of English versions our data demonstrate high reliability for Thai versions of the SSADDA and MINI in the diagnosis of OD. The high concordance between instruments supports the concurrent validity of the diagnosis. Either interview provides reliable valid OD diagnoses in Thai speaking Hmong individuals

Marques-Vidal P; Kutalik Z; Paccaud F; Bergmann S; Waeber G; Vollenweider P et al. Variant within the promoter region of the CHRNA3 gene associated with FTN dependence is not related to self-reported willingness to quit smoking. Nicotine & Tobacco Research 13(9): 833-839, 2011. (31 refs.)

Introduction: Common variation in the CHRNA5-CHRNA3-CHRNB4 gene region is robustly associated with smoking quantity. Conversely, the association between one of the most significant single nucleotide polymorphisms (SNPs; rs1051730 within the CHRNA3 gene) with perceived difficulty or willingness to quit smoking among current smokers is unknown. Methods: Cross-sectional study including current smokers, 502 women, and 552 men. Heaviness of smoking index (HSI), difficulty, attempting, and intention to quit smoking were assessed by questionnaire. Results: The rs1051730 SNP was associated with increased HSI (age, gender, and education-adjusted mean +/- SE: 2.6 +/- 0.1, 2.2 +/- 0.1, and 2.0 +/- 0.1 for AA, AG, and GG genotypes, respectively, p < .01). Multivariate logistic regression adjusting for gender, age, education, leisure-time physical activity, and personal history of cardiovascular or lung disease showed rs1051730 to be associated with higher smoking dependence (odds ratio [OR] and 95% CI for each additional A-allele: 1.38 [1.11-1.72] for smoking more than 20 cigarette equivalents/day; 1.31 [1.00-1.71] for an HSI >= 5 and 1.32 [1.05-1.65] for smoking 5 min after waking up) and borderline associated with difficulty to quit (OR = 1.29 [0.98-1.70]), but this relationship was no longer significant after adjusting for nicotine dependence. Also, no relationship was found with willingness (OR = 1.03 [0.85-1.26]), attempt (OR = 1.00 [0.83-1.20]), or preparation (OR = 0.95 [0.38-2.38]) to quit. Similar findings were obtained for other SNPs, but their effect on nicotine dependence was no longer significant after adjusting for rs1051730. Conclusions: These data confirm the effect of rs1051730 on nicotine dependence but failed to find any relationship with difficulty, willingness, and motivation to quit.

Martinotti G; Di Iorio G; Tedeschi D; De Berardis D; Niolu C; Janiri L et al. Prevalence and intensity of basic symptoms among cannabis users: An observational study. American Journal of Drug and Alcohol Abuse 37(2): 111-116, 2011. (53 refs.)

Background: It is difficult to establish whether people who are prone to psychosis are drawn to cannabis use or whether cannabis use truly increases the incidence of psychotic experiences. Objectives: The aim of our study was to evaluate, in a sample of healthy high school and university students, the presence and level of subjective experiences (SEs) and their relation to cannabis use. Methods: A total of 502 voluntary subjects were recruited; an anamnestic interview was administered to obtain socio-demographic information, cannabis use data, and psychiatric familial history. SEs were assessed using the Italian version of the Frankfurt Complaint Questionnaire (FCQ). Results: One hundred and fourteen subjects declared the use of cannabis: 20.5%% smoked more than 1 joint per week, and 71.9%% used cannabis for a period of more than 1 year. Cannabis users did not differ from the cannabis-free group in any of the 10 FCQ dimensions. Higher FCQ total scores were found in cannabis users with a familial history of psychiatric disorders respective to those without a psychiatric load (p < .05). Conclusions and scientific significance: In our study, SE intensity was not influenced by the use of cannabis. With regard to familial data, this is the first study to explore the relationship between SE and the presence of psychiatric problems in first-degree relatives. The association between FCQ intensity and psychiatric familial load may confirm the independence of these phenomena from the use of cannabis.

Matsusue A; Hara K; Kashiwagi M; Kageura M; Sugimura T; Kubo S. Genetic analysis of the rhabdomyolysis-associated genes in forensic autopsy cases of methamphetamine abusers. Legal Medicine 13(1): 7-11, 2011. (44 refs.)

Methamphetamine (MA) use sometimes causes rhabdomyolysis, which has been associated with mortality. We analyzed potential rhabdomyolysis-susceptibility genes from autopsy samples of 18 methamphetamine abusers. We examined mutations in the ryanodine receptor 1 (RYR 1), carnitine palmitoyl-transferase II (CPT II), very long-chain acyl-CoA dehydrogenase (VLCAD), and cytochrome P450 (CYP) 2D6 genes. Different RYR1 mutations that caused amino acid substitutions ((612)Ala > Thr and (4295)Ala > Val) were identified in 2 cases. In the CPT II gene, there was a new mutation ((545)Glu > Ala) in 1 case and there were mutations that did not change activity in 17 cases. In the VLCAD gene, there were mutations that did not change activity in 6 cases. In the CYP2D6 gene, homozygosity for CYP2D6*10, which is associated with significantly reduced metabolic activity, was found in 3 cases, while 2 cases carried a different previously unreported missense mutation ((344)Arg > Gln and (48)His > Tyr). RYR1 mutations and the new CPT II mutation identified in this study were not observed in a control group. Eighteen cases that were genetically analyzed were also investigated immunohistochemically to diagnose the possibility of rhabdomyolysis. However, there were no significant mutations that reduced enzyme activity in the suspected cases of rhabdomyolysis. These data suggested no obvious relationship between the genetic mutations observed in this study and rhabdomyolysis.

Meyer MR; Maurer HH. Absorption, distribution, metabolism and excretion pharmacogenomics of drugs of abuse. (review). Pharmacogenomics 12(2): 215-233, 2011. (220 refs.)

Pharmacologic and toxic effects of xenobiotics, such as drugs of abuse, depend on the genotype and phenotype of an individual, and conversely on the isoenzymes involved in their metabolism and transport. The current knowledge of such isoenzymes of frequently abused therapeutics such as opioids (oxycodone, hydrocodone, methadone, fentanyl, buprenorphine, tramadol, heroin, morphine and codeine), anesthetics (y-hydroxybutyric acid, propofol, ketamine and phencyclidine) and cognitive enhancers (methylphenidate and modafinil), and some important plant-derived hallucinogens (lysergide, salvinorin A, psilocybin and psilocin), as well as of nicotine in humans are summarized in this article. The isoenzymes (e.g., cytochrome P450, glucuronyltransferases, esterases and reductases) involved in the metabolism of drugs and some pharmacokinetic data are discussed. The relevance of such data is discussed for predicting possible interactions with other xenobiotics, understanding pharmacokinetic behavior and pharmacogenomic variations, assessing toxic risks,

Minnix JA; Robinson JD; Lam CY; Carter BL; Foreman JE; Vandenbergh DJ et al. The serotonin transporter gene and startle response during nicotine deprivation. Biological Psychology 86(1): 1-8, 2011. (80 refs.)

Affective startle probe methodology was used to examine the effects of nicotine administration and deprivation on emotional processes among individuals carrying at least one s allele versus those with the 1/1 genotype of the 5-Hydroxytryptamine (Serotonin) Transporter Linked Polymorphic Region, 5-HTTLPR in the promoter region of the serotonin transporter gene [solute ligand carrier family 6 member A4 (SLC6A4) or SERT]. Smokers (n = 84) completed four laboratory sessions crossing deprivation (12-h deprived vs. non-deprived) with nicotine spray (nicotine vs. placebo). Participants viewed affective pictures (positive, negative, neutral) while acoustic startle probes were administered. We found that smokers with the 1/1 genotype showed significantly greater suppression of the startle response when provided with nicotine vs. placebo than those with the s/s or s/1 genotypes. The results suggest that 1/1 smokers, who may have higher levels of the serotonin transporter and more rapid synaptic serotonin clearance, experience substantial reduction in activation of the defensive system when exposed to nicotine.

Motlagh MG; Sukhodolsky DG; Landeros-Weisenberger A; Katsovich L; Thompson N; Scahill L et al. Adverse effects of heavy prenatal maternal smoking on attentional control in children With ADHD. Journal of Attention Disorders 15(7): 593-603, 2011. (84 refs.)

Objective: Exposure to heavy maternal cigarette smoking in pregnancy and severe maternal psychosocial stress during pregnancy appear to be important risk factors for the development of ADHD. This study aimed to determine whether these perinatal risk factors were associated with neuropsychological deficits commonly seen in ADHD. Method: We examined the effect of these two risk factors on measures of attentional control, motor inhibition, visual-motor integration, and fine motor coordination in a group of 81 children with ADHD, aged from 8 to 18 years. The neuropsychological battery included the Connors' Continuous Performance Test (CPT), the Stroop Color-Word Interference Test, the Beery Visual-Motor Integration Test, and the Purdue Pegboard Test. Results: Heavy maternal smoking during pregnancy was associated with slower reaction times (p < .002), and reaction time variability (p < .007) on the CPT. Conclusions: This study suggests a persistent negative effect of heavy prenatal maternal smoking on attentional control in children with ADHD. Future studies should examine the neurobiological basis and determine the degree to which inherited genetic susceptibility factors contribute to this finding.

Munafo MR; Johnstone EC; Walther D; Uhl GR; Murphy MFG; Aveyard P. CHRNA3 rs1051730 genotype and short-term smoking cessation. Nicotine & Tobacco Research 13(10): 982-988, 2011. (35 refs.)

Introduction: The rs1051730 genetic variant within the CHRNA5-A3-B4 gene cluster is associated with heaviness of smoking and has recently been reported to be associated with likelihood of stopping smoking. We investigated the potential association of rs1051730 genotype with reduced likelihood of smoking cessation in 2 cohorts of treatment-seeking smokers in primary care in the United Kingdom. Methods: Data were drawn from 2 clinical trials on which DNA was available. One sample was a randomized placebo-controlled trial of nicotine transdermal patch and the other sample an open-label trial where all participants received nicotine transdermal patch. Smoking status was biochemically verified. Logistic regression was used to assess evidence for association in each sample, and data were combined within a meta-analysis. Results: There was evidence of association of rs1051730 genotype with short-term (4-week) cessation in our open-label trial sample but not our placebo-controlled trial sample. When combined in a meta-analysis, this effect remained. There was no evidence of association at later follow-up intervals. Adjustment for cigarette consumption and tobacco dependence did not alter these results substantially. Conclusions: Our data, taken together with previous recent studies, provide some support for a weak association between this variant and short-term smoking cessation in treatment-seeking smokers, which does not seem to operate only among those receiving nicotine replacement therapy. Moreover, the rs1051730 variant may not merely operate as a marker for dependence or heaviness of smoking.

Nikolov MA; Beltcheva O; Galabova A; Ljubenova A; Jankova E; Gergov G et al. No evidence of association between 118A > G OPRM1 polymorphism and heroin dependence in a large Bulgarian case-control sample. Drug and Alcohol Dependence 117(1): 62-65, 2011. (31 refs.)

The mu-opioid receptor is the primary site of action of most opioids. The 118A>G (rs1799971) polymorphism in exon 1 of the mu-opioid receptor gene (OPRM1) leads to an Asn40Asp amino acid change that affects a putative N-glycosylation site. It has been widely investigated for association with alcohol and drug dependence and pain sensitivity, with mixed results. The aim of the current study was to examine whether this polymorphism was associated with heroin dependence in a large Bulgarian cohort of 1842 active users and 1451 population controls. SNP genotyping was done using Real-Time PCR TaqMan technology. Association analyses were conducted, separately for Roma and non-Roma participants. Our results suggest that there is no direct effect of 118A>G genotype on the risk for heroin dependence among active heroin users.

Okahisa Y; Kodama M; Takaki M; Inada T; Uchimura N; Yamada M et al. Association study of two cannabinoid receptor genes, CNR1 and CNR2, with methamphetamine dependence. Current Neuropharmacology 9(1): 183-189, 2011. (41 refs.)

Several studies have suggested that the endocannabinoid system plays significant roles in the vulnerability to psychiatric disorders including drug abuse. To examine the possible association of the CNR1 and CNR2 genes, which encode cannabinoid receptors CB1 and CB2, with methamphetamine dependence, we investigated three single nucleotide polymorphisms (SNPs) (rs806379, rs1535255, rs2023239) in intron 2 of the CNR1 gene and a nonsynonymous SNP, Q63R, in the CNR2 gene. The study samples consisted of 223 patients with methamphetamine dependence and 292 age-and sex-matched controls. There were no significant differences between the patients and controls in genotypic or allelic distribution of any SNP of the CNR1 and CNR2 genes. We also analyzed the clinical features of methamphetamine dependence. Rs806379 of the CNR1 gene showed a significant association with the phenotype of latency of psychosis after the first consumption of methamphetamine. Patients with the T allele or T-positive genotypes (T/T or A/T) may develop a rapid onset of psychosis after methamphetamine abuse. The present study suggests a possibility that genetic variants of the CNR1 gene may produce a liability to the complication of psychotic state after abuse of methamphetamine; however, our findings need to be confirmed by future replications.

Okochi T; Kishi T; Ikeda M; Kitajima T; Kinoshita Y; Kawashima K et al. Genetic association analysis of NOS3 and methamphetamine-induced psychosis among Japanese. Current Neuropharmacology 9(1): 151-154, 2011. (15 refs.)

Endothelial nitric oxide synthase (NOS3) is one of the enzymes influencing nitric oxide (NO) function in the human brain. NO is a gaseous neurotransmitter that is involved in a variety of mechanisms in the central nervous system, such as N-methyl-D-aspartate receptor activation and oxidative stress. The evidence from animal pharmacological studies and postmortem studies supports an association between NO and psychotic disorders. Methamphetamine (METH) use disorder is a known psychotic disorder, and we therefore conducted a gene-based case-control study between tagging single nucleotide polymorphisms (SNPs) (rs2070744, rs1799983) in NOS3 and METH-induced psychosis in Japanese subjects (183 with METH-induced psychosis and 267 controls). Written informed consent was obtained from each subject. No significant association was found between any tagging SNP in NOS3 and METH-induced psychosis in the allele/genotype-wise or haplotype-wise analyses. In conclusion, we suggest that NOS3 might not contribute to the risk of METH-induced psychosis in the Japanese population.

Okumura T; Okochi T; Kishi T; Ikeda M; Kitajima T; Kinoshita Y et al. Genetic association analysis of NOS1 and methamphetamine-induced psychosis among Japanese. Current Neuropharmacology 9(1): 155-159, 2011. (18 refs.)

The neuronal nitric oxide synthase gene (NOS1) is located at 12q24, a susceptibility region for schizophrenia, and produces nitric oxide (NO). NO has been reported to play important roles as a gaseous neurotransmitter in brain. NO is a second messenger for the N-methyl-D aspartate (NMDA) receptor and is related to the dopaminergic system. Because the symptomatology of methamphetamine (METH) use disorder patients with psychosis is similar to that of patients with schizophrenia, NOS1 is a good candidate gene for METH-induced psychosis. Therefore, we conducted a case-control association study between NOS1 and METH-induced psychosis with Japanese subjects (183 with METH-induced psychosis patients and 519 controls). We selected seven SNPs (rs41279104, rs3782221, rs3782219, rs561712, rs3782206, rs6490121, rs2682826) in NOS1 from previous reports. Written informed consent was obtained from each subject. This study was approved by the Ethics Committee at Fujita Health University School of Medicine and each participating institute of the Japanese Genetics Initiative for Drug Abuse (JGIDA). No significant association was found between NOS1 and METH-induced psychosis in the allele/genotype-wise or haplotype-wise analyses. In conclusion, we suggest that NOS1 might not contribute to the risk of METH-induced psychosis in the Japanese population.

Park ER; Kleimann S; Youatt EJ; Lockhart A; Campbell EG; Levy DE et al. Black and White adults' perspectives on the genetics of nicotine addiction susceptibility. Addictive Behaviors 36(7): 769-772, 2011. (49 refs.)

Aims: Emerging research may soon lead to improved quit rates via genetically-tailored smoking cessation treatment. The purpose of this study was to explore individuals' beliefs and attitudes about genetic testing in this context, and how these may differ across racial groups. Design: Two site qualitative study. Methods: Eleven focus groups were conducted in 2007 with 51 Black and 55 White adult participants in Montgomery, AL and Baltimore, MD. Measurements: Questions were asked about smoking as an addiction, the role of genetics in nicotine addiction susceptibility, and undergoing genetic testing to receive tailored smoking cessation treatment. Data were analyzed using content analysis. Findings: Most participants believed that smoking was an addiction yet were unwilling to endorse the notion that genetics played a role in nicotine addiction susceptibility. However, 91% of White participants and 62% of Black participants indicated that they would likely take a genetic test that would match them to their optimal smoking cessation treatment. The primary potential benefit was a vague sense that additional knowledge about oneself would be of value. Primary barriers included disinterest and skepticism about the test, unwillingness to believe that genetics played a role in nicotine addiction or treatment response, and concerns about psychological consequences. Conclusions: The majority of participants, particularly Black participants, did not believe that genetics played a significant role in nicotine addiction susceptibility but were willing to undergo genetic testing. Participants identified some benefit to tailoring smoking treatment by genotype. However, participants also expressed skepticism about the test and concerns about its consequences; these issues would need to be addressed in the clinical encounter.

Perez-Stable EJ; Benowitz NL. Do biological differences help explain tobacco-related disparities? (commentary). American Journal of Health Promotion 25(5, Supplement S): s8-s10, 2011. (27 refs.)

This commentary notes that smoking behaviors vary by age, eductional level, economic status, gender/race/ethnicity and geographical education. Epidemiology studies have identified higher rates of smoking among men, whites, and AfricanAmericans, and those with less than high school education among nonimmigrants. Immigrants from Latin America and Asia tend to have lower rates of smoking, especially among women. In addition, nondaily smoking or smoking 5 or fewer cigarettes per day is more common among nonwhite smokers. This commentary raises questions about a possible genetic basis for these differences. Racial differences in nicotine metabolism have been identified. For example, AfricanAmericans metabolize and eliminate nicotine more slowly and inhale higher doses of nicotine per cigarette. Latinos of Mexican and Central American national origin metabolize nicotine at the same rate as whites and have a similar intake of nicotine. ChineseAmerican metabolize and clear nicotine more slowly and absorb less nicotine per cigareete. There is a brief review of other biological differences identified, in terms of cotinine levels. Also there are significant differnences in exposure to secondhand smoke and differences in serum cotinine levels of nonsmokers. Other questions raised are whether nicotine differences in metabolism affect cessation, and also genetic factors related to lung cancer.

Pomerleau OF; Pomerleau CS. Commentary on Haberstick, et al. (2011): Dizziness upon initial experimentation with cigarettes - implications for smoking persistence. (commentary). Addiction 106(2): 400-401, 2011. (8 refs.)

Ray B; Jackson C; Ducat E; Ho A; Hamon S; Kreek MJ. Effect of ethnicity, gender and drug use history on achieving high rates of affirmative informed consent for genetics research: Impact of sharing with a national repository. Journal of Medical Ethics 37(6): 374- 379, 2011. (23 refs.)

Aim: Genetic research representative of the population is crucial to understanding the underlying causes of many diseases. In a prospective evaluation of informed consent we assessed the willingness of individuals of different ethnicities, gender and drug dependence history to participate in genetic studies in which their genetic sample could be shared with a repository at the National Institutes of Health. Methods: Potential subjects were recruited from the general population through the use of flyers and referrals from previous participants and clinicians with knowledge of our study. They could consent to 11 separate choices so that they could specify how and with whom their genetic sample could be shared. Rates of affirmative consent were then analysed by gender, ethnicity and drug dependence history. Results: Of 1416 volunteers enrolled, 99.7% gave affirmative informed consent for studies of addiction conducted in our laboratory. No significant difference was found for participation in genetic studies conducted in our laboratory by gender, ethnicity or drug dependence history. Over all 11 questions, individuals with a history of drug use were more likely to agree to consent to participate in our study than were healthy volunteers. Conclusion: A high percentage of each category of gender, ethnicity and drug history, gave affirmative consent at all levels. The level of detail in and the amount of time spent reviewing the informed consent, and a relationship of trust with the clinical investigator may contribute to this outcome.

Reid A. Drug addiction finds its own niche. (editorial). Behavioral and Brain Sciences 34(6): 321-322, 2011. (0 refs.)

The evolutionary framework suggested by Muller & Schumann (M&S) can be extended further by considering drug-taking in terms of Niche Construction Theory (NCT). It is suggested here that genetic and environmental components of addiction are modified by cultural acceptance of the advantages of non-addicted drug taking and the legitimate supply of performance-enhancing drugs. This may then reduce the prevalence of addiction.

Rendu F; Peoc'h K; Berlin I; Thomas D; Launay JM. Smoking related diseases: The central role of monoamine oxidase. (review). International Journal of Environmental Research and Public Health 8(1): 136-147, 2011. (49 refs.)

Smoking is a major risk factor of morbidity and mortality. It is well established that monoamine oxidase (MAO) activity is decreased in smokers. Serotonin (5-HT), a major substrate for MAO that circulates as a reserve pool stored in platelets, is a marker of platelet activation. We recently reported that smoking durably modifies the platelet 5-HT/MAO system by inducing a demethylation of the MAO gene promoter resulting in high MAO protein concentration persisting more than ten years after quitting smoking. The present data enlarges the results to another MAO substrate, norepinephrine (NE), further confirming the central role of MAO in tobacco use-induced diseases. Thus, MAO could be a readily accessible and helpful marker in the risk evaluation of smoking-related diseases, from cardiovascular and pulmonary diseases to depression, anxiety and cancer. The present review implements the new finding of epigenetic regulation of MAO and suggests that smoking-induced MAO demethylation can be considered as a hallmark of smoking-related cancers similarly to other aberrant DNA methylations.

Rigbi A; Yakir A; Sarner-Kanyas K; Pollak Y; Lerer B. Why do young women smoke? VI. A controlled study of nicotine effects on attention: pharmacogenetic interactions. Pharmacogenomics Journal 11(1): 45-52, 2011. (46 refs.)

In prior studies we found that young, female smokers manifest poorer performance than non-smokers on attention-related tasks and that these findings can be moderated by variation in nicotinic acetylcholine receptor (nAChR) genes. We predicted that under controlled conditions (1) nicotine would improve functioning on attentional tasks in smokers who previously manifested relatively poor performance, and that (2) smokers who carry genetic variations associated with poorer attention performance would derive greater benefit from nicotine. To test these hypotheses, 31 young female smokers, who participated in our previous study, performed the Matching Familiar Figures Test (MFFT), Tower of London Test and Continuous Performance Task (CPT) in a double-blind, within-between subject design, placebo or nicotine (4 mg as gum) serving as the within factor and genetic profile as the between factor. Repeated measures ANCOVA controlling for attention deficit symptomatology, substance abuse and nicotine dependence showed better performance under nicotine among participants with higher levels of attention deficit symptoms (MFFT errors: P = 0.04; CPT commissions: P = 0.01) and nicotine dependence (CPT stability of response: P 0.04) and greater consumption of caffeine (CPT stability of response: P 0.04). An interactive effect of genetic profile was demonstrated for SNP rs2337980 in CHRNA7. These findings suggest that nicotine may have stronger short-term facilitating effects on attention in women who have more attention deficit symptoms and consume more nicotine and caffeine. This effect may be modified by a specific genetic make-up. Such individuals may be at increased risk for nicotine addiction and for greater difficulties in smoking cessation.

Robison AJ; Nestler EJ. Transcriptional and epigenetic mechanisms of addiction. Nature Reviews. Neuroscience 12(11): 623-637, 2011

Investigations of long-term changes in brain structure and function that accompany chronic exposure to drugs of abuse suggest that alterations in gene regulation contribute substantially to the addictive phenotype. Here, we review multiple mechanisms by which drugs alter the transcriptional potential of genes. These mechanisms range from the mobilization or repression of the transcriptional machinery - including the transcription factors DeltaFOSB, cyclic AMP-responsive element binding protein (CREB) and nuclear factor-kappaB (NF-kappaB) - to epigenetics - including alterations in the accessibility of genes within their native chromatin structure induced by histone tail modifications and DNA methylation, and the regulation of gene expression by non-coding RNAs. Increasing evidence implicates these various mechanisms of gene regulation in the lasting changes that drugs of abuse induce in the brain, and offers novel inroads for addiction therapy.

Russo P; Nastrucci C; Alzetta G; Szalai C. Tobacco habit: Historical, cultural, neurobiological, and genetic features of people's relationship with an addictive drug. Perspectives in Biology and Medicine 54(4): 557-577, 2011

This article reviews the cultural history of man's relationship with tobacco and the steps in the discovery of tobacco addiction. Nicotine dependence (ND) or nicotine addiction (NA), among other forms of drug addiction, continues to be a significant public health problem in the world, as it is associated with major severe diseases such as cardiovascular disease and cancer. Evidence for a genetic influence on smoking behavior and ND has prompted a search for susceptibility genes. Proof has recently accumulated that single nucleotide polymorphisms (SNPs) in the genetic region encoding the nicotinic acetylcholine receptor (nAChR) subunits alpha5, alpha3, and beta4 are associated with smoking and ND. In this review, we consider tobacco as the archetype of substance addiction and describe the evolution of the tobacco habit from elite users to lower socioeconomic abusers (by mass marketing and specific targeting of vulnerable groups by the tobacco industry) to exemplify detrimental behavior with major threats to public health. Finally, we discuss the reasons for the difficulty of quitting addictions/habits and highlight possible solutions.

Schnoll RA; Shields AE. Physician barriers to incorporating pharmacogenetic treatment strategies for nicotine dependence into clinical practice. (editorial). Clinical Pharmacology & Therapeutics 89(3): 345-347, 2011. (5 refs.)

Advances in genomics research may improve health outcomes by tailoring treatment according to patients' genetic profiles. The treatment of nicotine dependence, in particular, may soon encompass pharmacogenetic treatment models. Realizing the benefits of such treatment strategies may depend on physicians' preparedness to incorporate genetic testing into clinical practice. This article describes barriers to clinical integration of pharmacogenetic treatments that will need to be addressed to realize the benefits of individualized smoking-cessation treatment.

Seddon JM; Reynolds R; Shah HR; Rosner B. Smoking, dietary betaine, methionine, and vitamin D in monozygotic twins with discordant macular degeneration: Epigenetic implications. Ophthalmology 118(7): 1386-1394, 2011. (52 refs.)

Objective: We evaluated monozygotic twin pairs with discordant age-related macular degeneration (AMD) phenotypes to assess differences in behavioral and nutritional factors. Design: Case series. Participants: Caucasian male twin pairs from the United States Twin Study of Macular Degeneration. Methods: Twin pairs were genotyped to confirm monozygosity. Ocular characteristics were evaluated based on fundus photographs using the Wisconsin Grading System and a 5-grade Clinical Age-Related Maculopathy Staging System. We selected twin pairs discordant in each of the following phenotypic categories: Stage of AMD (n = 28), drusen area (n = 60), drusen size (n = 40), and increased pigment area (n = 56). The Wilcoxon signed-rank test and linear regression were used to assess associations between behavioral and nutritional characteristics and each phenotype within discordant twin pairs. Main Outcome Measures: Differences in smoking and dietary factors within twin pairs discordant for stage of AMD, drusen area, drusen size, and pigment area. Results: Representative fundus photographs depict the discordant phenotypes. Pack-years of smoking were higher for the twin with the more advanced stage of AMD (P = 0.05). Higher dietary intake of vitamin D was present in the twins with less severe AMD (P = 0.01) and smaller drusen size (P = 0.05) compared with co-twins, adjusted for smoking and age. Dietary intakes of betaine and methionine were significantly higher in the twin with lower stage of AMD (P = 0.009) and smaller drusen area (P = 0.03), respectively. Conclusions: The twin with the more advanced stage of AMD, larger drusen area, drusen size, and pigment area tended to be the heavier smoker. The twin with the earlier stage of AMD, smaller drusen size and area, and less pigment tended to have higher dietary vitamin D, betaine, or methionine intake. Results suggest that behavioral and nutritional factors associated with epigenetic mechanisms are involved in the etiology of AMD, in addition to genetic susceptibility.

Shields AE. Ethical concerns related to developing pharmacogenomic treatment strategies for addiction. Addiction Science & Clinical Practice 6(1): unpaginated, 2011

Pharmacogenomics (PGx) research is poised to enable physicians to identify optimally effective treatments for individual substance abusers based on their genetic profiles. This paper addresses ethical issues related to PGx treatment strategies for addiction, focusing especially on the use of race variables in genomics research and ensuring equitable access to novel PGx treatments. Unless the field addresses the ethical challenges posed by these issues, PGx treatment innovations for addiction threaten to exacerbate already dramatic disparities in the burden of drug dependence for minority and other underserved populations.

Public Domain

Siedlinski M; Cho MH; Bakke P; Gulsvik A; Lomas DA; Anderson W et al. Genome-wide association study of smoking behaviours in patients with COPD. Thorax 66(10): 894-902, 2011. (41 refs.)

Background: Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease (COPD) and COPD severity. Previous genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with the number of cigarettes smoked per day (CPD) and a dopamine beta-hydroxylase (DBH) locus associated with smoking cessation in multiple populations. Objective To identify SNPs associated with lifetime average and current CPD, age at smoking initiation, and smoking cessation in patients with COPD. Methods GWAS were conducted in four independent cohorts encompassing 3441 ever-smoking patients with COPD (Global Initiative for Obstructive Lung Disease stage II or higher). Untyped SNPs were imputed using the HapMap (phase II) panel. Results from all cohorts were meta-analysed. Results: Several SNPs near the HLA region on chromosome 6p21 and in an intergenic region on chromosome 2q21 showed associations with age at smoking initiation, both with the lowest p = 2x10(-7). No SNPs were associated with lifetime average CPD, current CPD or smoking cessation with p<10(-6). Nominally significant associations with candidate SNPs within cholinergic receptors, nicotinic, alpha 3/5 (CHRNA3/CHRNA5; eg, p=0.00011 for SNP rs1051730) and cytochrome P450, family 2, subfamily A, polypeptide 6 (CYP2A6; eg, p=2.78x10(-5) for a non-synonymous SNP rs1801272) regions were observed for lifetime average CPD, however only CYP2A6 showed evidence of significant association with current CPD. A candidate SNP (rs3025343) in DBH was significantly (p=0.015) associated with smoking cessation. Conclusion: The authors identified two candidate regions associated with age at smoking initiation in patients with COPD. Associations of CHRNA3/CHRNA5 and CYP2A6 loci with CPD and DBH with smoking cessation are also likely of importance in the smoking behaviours of patients with COPD.

Sobczyk-Kopciol A; Broda G; Wojnar M; Kurjata P; Jakubczyk A; Klimkiewicz A et al. Inverse association of the obesity predisposing FTO rs9939609 genotype with alcohol consumption and risk for alcohol dependence. Addiction 106(4): 739-748, 2011. (51 refs.)

PU Pacini Editore To investigate whether the FTO rs9939609 A allele (a risk factor for obesity) is associated with measures of alcohol consumption. Design: Population-based cross-sectional study and two case-control studies. Setting: Poland and the Warsaw area. Participants: A total of 6584 subjects from the WOBASZ survey and two cohorts of alcohol-dependent patients (n = 145 and n = 148). Measurements: Questionnaire data analysis, rs9939609 typing. Findings: Among individuals drinking alcohol, the obesity-associated AA genotype was also associated with lower total ethanol consumption [sex-, age- and body mass index (BMI)-adjusted difference: 0.21 g/day, P = 0.012] and distinct drinking habits with relatively low frequency of drinks but larger volume consumed at a time as evidenced by (i) association between AA and frequency/amount of typical drinks (P = 0.023, multiple logistic regression analysis); (ii) inverse correlation between AA and drink frequency adjusted for drink size (P = 0.007 for distilled spirits, P = 0.018 for beer); (iii) decreased frequency of AA [odds ratio (OR) = 0.46, P = 0.0004] among those who drank small amounts of distilled spirits (< 100 ml at a time) but frequently (>= 1-2 times/week). A decrease of AA was also found in both cohorts of alcohol-dependent patients versus geographically matched subjects from WOBASZ yielding a pooled estimate of OR = 0.59, confidence interval (CI): 0.40-0.88, P = 0.008. Exploratory analysis showed that those with rs9939609 AA reported lower (by 1.22) mean number of cigarettes/day during a year of most intense smoking (P = 0.003) and were older at start of smoking by 0.44 years (P = 0.016). Conclusions: The FTO AA genotype, independently from its effect on BMI, is associated with measures of ethanol consumption and possibly tobacco smoking.

Somaini L; Donnini C; Manfredini M; Raggi MA; Saracino MA; Gerra ML et al. Adverse childhood experiences (ACEs), genetic polymorphisms and neurochemical correlates in experimentation with psychotropic drugs among adolescents. (review). Neuroscience and Biobehavioral Reviews 35(8): 1771-1778, 2011. (104 refs.)

Epidemiological and clinical data show frequent associations between adverse childhood experiences (ACEs) and substance abuse susceptibility particularly in adolescents. A large body of evidences suggests that the possible dysregulation of neuroendocrine responses as well as neurotransmitters function induced by childhood traumatic experiences and emotional neglect could constitute one of the essential biological changes implementing substance abuse vulnerability. Moreover, genotype variables and its environment interactions have been associated with an increased risk for early onset substance abuse. In this paper we present several data that support the hypothesis of the involvement of hypothalamus-pituitary-adrenal (HPA) axis in mediating the combined effect of early adverse experiences and gene variants affecting neurotransmission. The presented data also confirm the relationship between basal plasma levels of cortisol and ACTH, on the one hand, and retrospective measures of neglect during childhood on the other hand: the higher the mother and father neglect (CECA-Q) scores are, the higher the plasma levels of the two HPA hormones are. Furthermore, such positive relationship has been proved to be particularly effective and important when associated with the "S" promoter polymorphism of the gene encoding the 5-HTT transporter, both in homozygote and heterozygote individuals.

Sommer A; Blanton SH; Weymouth K; Alvarez C; Richards BS; Barnes D et al. Smoking, the xenobiotic pathway, and clubfoot. Birth Defects Research. Part A: Clinical and Molecular Teratology 91(1): 20-28, 2011. (85 refs.)

BACKGROUND: Isolated clubfoot is a common orthopedic birth defect that affects approximately 135,000 newborns worldwide. It is characterized by ankle equinus, hindfoot varus, and forefoot adductus. Although numerous studies suggest a multifactorial etiology, the specific genetic and environmental components have yet to be delineated. Maternal smoking during pregnancy is the only common environmental factor consistently shown to increase the risk for clubfoot. Moreover, a positive family history of clubfoot, in conjunction with maternal smoking, increases the risk 20-fold. These findings suggest that genetic variation in smoking metabolism (xenobiotic) genes may increase susceptibility to clubfoot. Based on this reasoning, we interrogated eight candidate genes from the xenobiotic metabolism. METHODS: Twenty-two single-nucleotide polymorphisms and two null alleles in these genes (CYP1A1, CYP1A2, CYP1B1, CYP2A6, EPHX1, NAT2, GSTM1, and GSTT1) were genotyped in a dataset composed of non-Hispanic white and Hispanic multiplex and simplex families. RESULTS: Only rs1048943/CYP1A1 had significantly altered transmission in the aggregate and multiplex non-Hispanic white datasets (p = 0.003 and p = 0.009, respectively). Perturbation of CYP1A1 can cause an increase in harmful, adduct-forming metabolic intermediates. A significant interaction between EPHX1 and NAT2 was also found (p = 0.007). Importantly, for CYP1A2, significant maternal (p = 0.03; relative risk [RR] = 1.24; 95% confidence interval [CI], 1.04-1.44) and fetal (p = 0.01; RR = 1.33; 95% CI, 1.13-1.54) genotypic effects were identified, suggesting that both maternal and fetal genotypes can negatively impact limb development. No association was found between maternal smoking status and variation in xenobiotic metabolism genes. CONCLUSION: Together, these results suggest that xenobiotic metabolism genes are unlikely to play a major role in clubfoot; however, perturbation of this pathway may still play a contributory role.

Steliga MA; Dresler CM. Epidemiology of lung cancer: Smoking, secondhand smoke, and genetics. Surgical Oncology Clinics of North America 20(4): 605-+, 2011. (27 refs.)

The link between smoking and development of lung cancer has been demonstrated, not only for smokers but also for those exposed to secondhand smoke. Despite the obvious carcinogenic effects of tobacco smoking, not all smokers develop lung cancer, and conversely some nonsmokers can develop lung cancer in the absence of other environmental risk factors. A multitude of genetic factors are beginning to be explored that interact with environmental exposure to alter the risk of developing this deadly disease. By more fully appreciating the complex interrelationship between genetics and other risks the development of lung cancer can be more completely understood.

Tettamanti G; Altman D; Pedersen NL; Bellocco R; Milsom I; Iliadou AN. Effects of coffee and tea consumption on urinary incontinence in female twins. International Journal of Obstetrics and Gynaecology 118(7): 806- 813, 2011. (25 refs.)

Objectives: To assess the effect of coffee and tea consumption on symptoms of urinary incontinence. Design: Population-based study. Setting: The Swedish Twin Register. Population: In 2005, all twins born between 1959 and 1985 in Sweden (n = 42 852) were invited to participate in a web-based survey to screen for common complex diseases and common exposures. The present study was limited to female twins with information about at least one urinary symptoms and coffee and tea consumption (n = 14 031). Main outcome measure: The association between coffee and tea consumption and urinary incontinence, as well as nocturia, was estimated as odds ratios (ORs) with 95% confidence intervals. Results: Women with a high coffee intake were at lower risk of any urinary incontinence (OR 0.78, 95% CI 0.64-0.98) compared with women not drinking coffee. Coffee intake and incontinence subtypes showed no significant associations whereas high tea consumption was specifically associated with a risk for overactive bladder (OR 1.34, 95% CI 11.07-1.67) and nocturia (OR 1.18, 95% CI 1.01-1.38). Results from co-twin control analysis suggested that the associations observed in logistic regression were mainly the result of familial effects. Conclusions: This study suggests that coffee and tea consumption has a limited effect on urinary incontinence symptoms. Familial and genetic effects may have confounded the associations observed in previous studies.

Thome J; Hassler F; Zachariou V. Gene therapy for psychiatric disorders. (review). World Journal of Biological Psychiatry 12(Supplement 1): 16-18, 2011. (16 refs.)

There is no indication that gene therapy can be applied in psychiatric patients any time soon. However, there are several promising developments on the level of experimental neuroscience indicating that gene therapy approaches have an effect in animal models of several psychiatric disorders including drug addiction, affective disorders, psychoses and dementia, modifying behavioural parameters via interventions on the molecular and cellular level. However, before gene therapy in psychiatric disorders can be considered on the human level, not only neurobiological and technical problems need to be overcome, but also important ethical questions answered.

Uhl GR; Walther D; Behm FM; Rose JE. Menthol preference among smokers: Association with TRPA1 variants. Nicotine & Tobacco Research 13(12): 1311-1315, 2011. (23 refs.)

Introduction: Preference for smoking menthol cigarettes differs from individual to individual and population to population in ways that may provide higher levels of nicotine intake and contribute to smoking's morbidity and mortality. Menthol acts at sites that include the transient receptor potential (TRP) A1 channel that is expressed by nociceptors in the lung and airways, suggesting that individual and population differences in TRPA1 sequences might contribute to observed differences in menthol preference among smokers. Methods: We have thus sought association between menthol preference and common variants in the TRPA1 gene in heavier and lighter European-American smokers. Smokers were recruited for studies of smoking cessation in North Carolina and of substance abuse genetics in Maryland. Results: A common TRPA1 haplotype is defined by 1 missense and 10 intronic single nucleotide polymorphisms that display significant (. 006 < p < .05; chi(2)) association with preference for mentholated cigarettes in heavy smokers (odds ratio ca. 1.3). There are smaller trends in the same direction in lighter smokers. Conclusions: This TRPA1 haplotype provides a novel biological basis for individual differences in menthol preference and possibly for actions of other agents that act at TRPA1.

van Winkel R. Family-based analysis of genetic variation underlying psychosis-inducing effects of cannabis sibling analysis and proband follow-up. Archives of General Psychiatry 68(2): 148-157, 2011. (60 refs.)

Context: Individual differences exist in sensitivity to the psychotomimetic effect of cannabis; the molecular genetic basis underlying differential sensitivity remains elusive. Objective: To investigate whether selected schizophrenia candidate single-nucleotide polymorphisms (SNPs) moderate effects of cannabis use. Design: Interactions between recent cannabis use, determined by urinalysis results, and 152 SNPs in 42 candidate genes were examined in 740 unaffected siblings of 801 patients with psychosis to examine genetic moderation of the association between Structured Interview for Schizotypy-Revised positive schizotypy and recent cannabis use (at-risk paradigm). The SNPs showing Bonferroni-adjusted association in the at-risk paradigm were used in a case-only analysis in the 801 patients, as well as in a case-sibling and case-control analysis (using 419 controls) focusing on genetic moderation of developmental effects of cannabis on later psychotic disorder. Setting: The Netherlands and Flanders, Belgium. Participants: Eight hundred one patients with psychosis and their 740 unaffected siblings. Main Outcome Measure: Significant interaction between any of the selected SNPs and cannabis in the at-risk paradigm, followed by selective case-only, casesibling, and case-control analyses. Results: In the unaffected siblings, 16 SNPs in 12 genes showed significant interaction at P<.05, 3 of which survived correction for multiple testing (P<.0003), situated in AKT1 (rs2494732 and rs1130233) and LRRTM1 (rs673871). Follow-up analysis supported AKT1 rs2494732 X cannabis interaction in the case-only (beta=0.20; P=.007), case-sibling (interaction P=.040), and case-control (interaction P=.057) analyses, with individuals with C/C genotypes having an approximately 2-fold odds of being diagnosed with a psychotic disorder when having used cannabis. In the unaffected siblings, the AKT1 X cannabis interaction explained 2.2% additional variance in schizotypy in the whole sample and 19.0% additional variance in the exposed siblings with recent cannabis use. Conclusions: Genetic variation in AKT1 may mediate both short-term as well as longer-term effects on psychosis expression associated with use of cannabis, possibly through a mechanism of cannabinoid-regulated AKT1/GSK-3 signaling downstream of the dopamine D-2 receptor.

Ware JJ; van den Bree MBM; Munafo MR. Association of the CHRNA5-A3-B4 gene cluster with heaviness of smoking: A meta-analysis. (review). Nicotine & Tobacco Research 13(12): 1167-1175, 2011. (58 refs.)

Variation in the CHRNA5-A3-B4 gene cluster is a promising candidate region for smoking behavior and has been linked to multiple smoking-related phenotypes (e.g., nicotine dependence) and diseases (e.g., lung cancer). Two single nucleotide polymorphisms (SNPs), rs16969968 in CHRNA5 and rs1051730 in CHRNA3, have generated particular interest. We evaluated the published evidence for association between rs16969968 (k = 27 samples) and rs1051730 (k = 44 samples) SNPs with heaviness of smoking using meta-analytic techniques. We explored which SNP provided a stronger genetic signal and investigated study-level characteristics (i.e., ancestry, disease state) to establish whether the strength of association differed across populations. We additionally tested for small study bias and explored the impact of year of publication. Meta-analysis indicated compelling evidence of an association between the rs1051730/rs16966968 variants and daily cigarette consumption (fixed effects: B = 0.91, 95% CI = 0.77, 1.06, p < .001; random effects: B = 1.01, 95% CI = 0.81, 1.22, p < .001), equivalent to a per-allele effect of approximately 1 cigarette/day. SNP rs1051730 was found to provide a stronger signal than rs16966968 in stratified analyses (p(diff) = .028), although this difference was only qualitatively observed in the subset of samples that provided data on both SNPs. While the functional relevance of rs1051730 is unknown, it may be a strong tagging SNP for functional haplotypes in this region.

Wassenaar CA; Dong Q; Wei QY; Amos CI; Spitz MR; Tyndale RF. Relationship between CYP2A6 and CHRNA5-CHRNA3-CHRNB4 variation and smoking behaviors and lung cancer risk. Journal of the National Cancer Institute 103(17): 1342-1346, 2011. (26 refs.)

Genetic variations in the CYP2A6 nicotine metabolic gene and the CHRNA5-CHRNA3-CHRNB4 (CHRNA5-A3-B4) nicotinic gene cluster have been independently associated with lung cancer. With genotype data from ever-smokers of European ancestry (417 lung cancer patients and 443 control subjects), we investigated the relative and combined associations of polymorphisms in these two genes with smoking behavior and lung cancer risk. Kruskal-Wallis tests were used to compare smoking variables among the different genotype groups, and odds ratios (ORs) for cancer risk were estimated using logistic regression analysis. All statistical tests were two-sided. Cigarette consumption (P < .001) and nicotine dependence (P = .036) were the highest in the combined CYP2A6 normal metabolizers and CHRNA5-A3-B4 AA (tag single-nucleotide polymorphism rs1051730 G>A) risk group. The combined risk group also exhibited the greatest lung cancer risk (OR = 2.03; 95% confidence interval [CI] = 1.21 to 3.40), which was even higher among those who smoked 20 or fewer cigarettes per day (OR = 3.03; 95% CI = 1.38 to 6.66). Variation in CYP2A6 and CHRNA5-A3-B4 was independently and additively associated with increased cigarette consumption, nicotine dependence, and lung cancer risk. CYP2A6 and CHRNA5-A3-B4 appear to be more strongly associated with smoking behaviors and lung cancer risk, respectively.

Watanabe MAE; Nunes SOV; Amarante MK; Guembarovski RL; Oda JMM; De Lima KWA; Fungaro MHP. Genetic polymorphism of serotonin transporter 5-HTTLPR: involvement in smoking behaviour. (review). Journal of Genetics 90(1): 179-185, 2011. (70 refs.)

Data suggest that the serotonin (5-hydroxytryptamine, 5-HT) system is implicated in the pathogenesis of multiple neuropsychiatric disorders and may also be involved in smoking behaviour since nicotine increases brain serotonin secretion. It is known that smoking behaviour is influenced by both genetic and environmental factors. The present review examines the role of the serotonin transporter gene (5-HTT) in smoking behaviour and investigating studies that showed association of 5-HTT gene with smoking. This study discusses a polymorphism which has been investigated by many researchers, as the bi-allelic insertion/deletion polymorphism in the 5'-flanking promoter region (5-HTTLPR). This gene has received considerable attention in attempts to understand the molecular determinants of smoking. Therefore, in the present study, the relationship between genetic polymorphism of serotonin transporter in smoking behaviour is reviewed considering the interactive effect of genetic factors.

Wehby GL; Fletcher JM; Lehrer SF; Moreno LM; Murray JC; Wilcox A; Lie RT. A genetics instrumental variables analysis of the effects of prenatal smoking on birth weight: Evidence from two samples. Biodemography and Social Biology 57(1, special issue): 3- 32, 2011. (73 refs.)

There is a large literature showing the detrimental effects of prenatal smoking on birth and childhood health outcomes. It is somewhat unclear, though, whether these effects are causal or reflect other characteristics and choices by mothers who choose to smoke that may also affect child health outcomes or biased reporting of smoking. In this paper, we use genetic markers that predict smoking behaviors as instruments to address the endogeneity of smoking choices in the production of birth and childhood health outcomes. Our results indicate that prenatal smoking produces more dramatic declines in birth weight than estimates that ignore the endogeneity of prenatal smoking, which is consistent with previous studies with non-genetic instruments. We use data from two distinct samples from Norway and the United States with different measured instruments and find nearly identical results. The study provides a novel application that can be extended to study several behavioral impacts on health and social and economic outcomes.

White MJ; Young RM; Morris CP; Lawford BR. Cigarette smoking in young adults: The influence of the HTR2A T102C polymorphism and punishment sensitivity. Drug and Alcohol Dependence 114(2-3): 140- 146, 2011. (52 refs.)

Background: The C allele of a common polymorphism of the serotonin 2A receptor (HTR2A) gene, T102C, results in reduced synthesis of 5-HT2A receptors and has been associated with current smoking status in adults. The -1438A/G polymorphism, located in the regulatory region of this gene, is in linkage disequilibrium with T102C, and the A allele is associated with increased promoter activity and with smoking in adult males. We investigated the contributions of the HTR2A gene, chronic psychological stress, and impulsivity to the prediction of cigarette smoking status and dependence in young adults. Methods: T102C and -1438A/G genotyping was conducted on 132 healthy Caucasian young adults (47 smokers) who completed self-report measures of chronic stress, depressive symptoms, impulsive personality and cigarette use. Results: A logistic regression analysis of current cigarette smoker user status, after adjusting for gender, depressive symptom severity and chronic stress, indicated that the T102C TT genotype relative to the CC genotype (OR = 7.53), and lower punishment sensitivity (OR = 0.91) were each significant predictive risk factors. However, for number of cigarettes smoked, only lower punishment sensitivity was a significant predictor (OR = 0.81). Conclusions: These data indicate the importance of the T102C polymorphism to tobacco use but not number of cigarettes smoked for Caucasian young adults. Future studies should examine whether this is explained by effects of nicotine on the serotonin system. Lower punishment sensitivity increased risk of both smoking and of greater consumption, perhaps via a reduced sensitivity to cigarette health warnings and negative physiological effects.

Wong CCY; Mill J; Fernandes C. Drugs and addiction: An introduction to epigenetics. (review). Addiction 106(3): 480-489, 2011. (74 refs.)

Addiction is a debilitating psychiatric disorder, with a complex aetiology involving the interaction of inherited predispositions and environmental factors. Emerging evidence suggests that epigenetic alterations to the genome, including DNA methylation and histone modifications, are important mechanisms underlying addiction and the neurobiological response to addictive substances. In this review, we introduce the reader to epigenetic mechanisms and describe a potential role for dynamic epigenetic changes in mediating addictive behaviours via long-lasting changes in gene expression. We summarize recent findings from both molecular and behavioural experiments elucidating the role of epigenetic changes in mediating the addictive potential of various drugs of abuse, including cocaine, amphetamine and alcohol. The implications of these findings for molecular studies of addiction and the future development of novel therapeutic interventions are also discussed.

Yang BZ; Han SZ; Kranzler HR; Farrer LA; Gelernter J. A genomewide linkage scan of cocaine dependence and major depressive episode in two populations. Neuropsychopharmacology 36(12): 2422-2430, 2011. (50 refs.)

Cocaine dependence (CD) and major depressive episode (MDE) frequently co-occur with poorer treatment outcome and higher relapse risk. Shared genetic risk was affirmed; to date, there have been no reports of genomewide linkage scans (GWLSs) surveying the susceptibility regions for comorbid CD and MDE (CD MDE). We aimed to identify chromosomal regions and candidate genes susceptible to CD, MDE, and CD MDE in African Americans (AAs) and European Americans (EAs). A total of 1896 individuals were recruited from 384 AA and 355 EA families, each with at least a sibling-pair with CD and/or opioid dependence. Array-based genotyping of about 6000 single-nucleotide polymorphisms was completed for all individuals. Parametric and non-parametric genomewide linkage analyses were performed. We found a genomewide-significant linkage peak on chromosome 7 at 183.4 cM for non-parametric analysis of CD MDE in AAs (lod = 3.8, genomewide empirical p = 0.016; point-wise p = 0.00001). A nearly genomewide significant linkage was identified for CD MDE in EAs on chromosome 5 at 14.3 cM (logarithm of odds (lod) = 2.95, genomewide empirical p = 0.055; point-wise p = 0.00012). Parametric analysis corroborated the findings in these two regions and improved the support for the peak on chromosome 5 so that it reached genomewide significance (heterogeneity lod = 3.28, genomewide empirical p = 0.046; point-wise p = 0.00053). This is the first GWLS for CD MDE. The genomewide significant linkage regions on chromosomes 5 and 7 harbor four particularly promising candidate genes: SRD5AI UBE3C, PTPRN2, and VIPR2. Replication of the linkage findings in other populations is warranted, as is a focused analysis of the genes located in the linkage regions implicated here.

Yoshimura T; Usui H; Takahashi N; Yoshimi A; Saito S; Aleksic B et al. Association analysis of the GDNF gene with methamphetamine use disorder in a Japanese population. (review). Progress In Neuro-Psychopharmacology & Biological Psychiatry 35(5, special issue): 1268-1272, 2011. (32 refs.)

Methamphetamine (MAP) dependence is a highly heritable and aberrant dopaminergic signaling that has been implicated in the disease. Glial cell line-derived neurotrophic factor (GDNF), which plays an important role in the survival of dopaminergic neurons, may be involved in this disorder. In this study, we examined the association between GDNF and MAP dependence using a Japanese population-based sample. We selected eight single nucleotide polymorphisms (SNPs) in the GDNF locus for the association analysis. When patients with MAP dependence were divided into two subgroups consisting of multi-substance and MAP-only users, we detected a significant association between these two groups and the tagging SNP, rs2910704 (after Bonferroni's correction; allele P = 0.034). Thus, GDNF is likely to be related to the severity of MAP use in the Japanese population.

Zuo LJ; Gelernter J; Zhang CK; Zhao HY; Lu LG; Kranzler HR et al. Genome-wide association study of alcohol dependence implicates KIAA0040 on chromosome 1q. Neuropsychopharmacology 37(2): 557-566, 2012. (31 refs.)

Previous studies using SAGE (the Study of Addiction: Geneticsics and Environment) and COGA (the Collaborative Study on the Geneticsics of Alcoholism) genome-wide association study (GWAS) data sets reported several risk loci for alcohol dependence (AD), which have not yet been well replicated independently or confirmed by functional studies. We combined these two data sets, now publicly available, to increase the study power, in order to identify replicable, functional, and significant risk regions for AD. A total of 4116 subjects (1409 European-American (EA) cases with AD, 1518 EA controls, 681 African-American (AA) cases, and 508 AA controls) underwent association analysis. An additional 443 subjects underwent expression quantitative trait locus (eQTL) analysis. Genome-wide association analysis was performed in EAs to identify significant risk genes. All available markers in the genome-wide significant risk genes were tested in AAs for associations with AD, and in six HapMap populations and two European samples for associations with gene expression levels. We identified a unique genome-wide significant gene-KIAA0040-that was enriched with many replicable risk SNPs for AD, all of which had significant cis-acting regulatory effects. The distributions of -log(p) values for SNP-disease and SNP-expression associations for all markers in the TNN-KIAA0040 region were consistent across EAs, AAs, and five HapMap populations (0.369 <= r <= 0.824; 2.8 x 10(-9)<= p <= 0.032). The most significant SNPs in these populations were in high LD, concentrating in KIAA0040. Finally, expression of KIAA0040 was significantly (1.2 x 10(-11)<= p <= 1.5 x 10(-6)) associated with the expression of numerous genes in the neurotransmitter systems or metabolic pathways previously associated with AD. We concluded that KIAA0040 might harbor a causal variant for AD and thus might directly contribute to risk for this disorder. KIAA0040 might also contribute to the risk of AD via neurotransmitter systems or metabolic pathways that have previously been implicated in the pathophysiology of AD. Alternatively, KIAA0040 might regulate the risk via some interactions with flanking genes TNN and TNR. TNN is involved in neurite outgrowth and cell migration in hippocampal explants, and TNR is an extracellular matrix protein expressed primarily in the central nervous system.