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CORK Bibliography: Genetics and Alcohol Use

89 citations. July 2011 to present

Prepared: March 2012

Acheson A; Richard DM; Mathias CW; Dougherty DM. Adults with a family history of alcohol related problems are more impulsive on measures of response initiation and response inhibition. Drug and Alcohol Dependence 117(2-3): 198-203, 2011. (58 refs.)

Background: Previous studies have found individuals with family histories of alcohol use disorders are more impulsive on some but not all laboratory behavioral measures, suggesting deficits on specific forms of impulse control. However, drawing conclusions is tenuous because these different measures have not been administered together in the same group of participants. Methods: In the present study, we compared healthy 21-35 year old adults with family histories of alcohol related problems (FHAP+) or without such histories (FHAP-) on behavioral measures of response inhibition, response initiation, and consequence sensitivity impulsivity. FHAP+ (n = 36) and FHAP- (n = 36) participants were compared on performance on the Immediate Memory Task (IMT, response initiation), GoStop Impulsivity Paradigm (GoStop, response inhibition), Two Choice Impulsivity Paradigm (TCIP, consequence sensitivity) and Single Key Impulsivity Paradigm (SKIP, consequence sensitivity). Results: FHAP+ individuals were more impulsive on the IMT and GoStop but not on the TCIP or SKIP. Conclusions: These results suggest that response initiation and response inhibition impulsivity are increased in individuals with family histories of alcohol related problems despite not having alcohol or drug use disorders themselves. In contrast, increased consequence sensitivity impulsivity may be associated with additional risk factors such as more severe family histories of alcohol use disorders, or it may be increased as a consequence of heavy drug or alcohol use.

Agrawal A; Lynskey MT; Todorov AA; Schrage AJ; Littlefield AK; Grant JD et al. A candidate gene association study of alcohol consumption in young women. Alcoholism: Clinical and Experimental Research 35(3): 550-558, 2011. (55 refs.)

Background: Excessive alcohol consumption contributes to significant morbidity and mortality. Heritable influences contribute to 50% of the variation in alcohol consumption, suggesting the important role of genes. We used data on a previously defined alcohol consumption factor score in a sample of 827 young women to investigate association with 1,014 single-nucleotide polymorphisms in genes related to addiction. Methods: Data were drawn from the Missouri Adolescent Female Twin Study (MOAFTS) with replication in the college drinking sample (CDS). Genotypic and phenotypic data were available on 827 MOAFTS and 100 CDS women of European-American ancestry. Data on 1,014 single-nucleotide polymorphisms (SNPs) across 130 genes related to addiction were utilized. Association was conducted in QTDT, which allows for identity-by-descent information to account accurately for twin status in the analysis. The total association variance components model was used, with specification of variance components for relatedness in MOAFTS. Results: The top signals included clusters of SNPs in tryptophan hydroxylase 2 (TPH2) (e.g., rs1386496, p = 0.0003) and dopa decarboxylase (DDC) (e.g., rs3779084, p = 0.0008), genes that encode proteins responsible for serotonin synthesis. Additional polymorphisms in ADH1B, ADH1C, ADH7, and ADH1A1 were also associated at p < 0.05. The false discovery rate for the top signal (p = 0.0003) was 0.15, suggesting nominal significance only. Replication was limited and noted for 2 SNPs in ADH1C. Conclusions: While no results survive the burden of multiple testing, nominal findings in TPH2 and DDC suggest the potential role of the serotonin synthesis pathway in alcohol consumption.

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.

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.

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.

Capone C; Kahler CW; Swift RM; O'Malley SS. Does family history of alcoholism moderate naltrexone's effects on alcohol use? Journal of Studies on Alcohol and Drugs 72(1): 135-140, 2011. (32 refs.)

Objective: Primary outcomes from the COMBINE Study indicated support for naltrexone (Revia) on measures of abstinence and time to heavy drinking; however, effect sizes were modest. The delineation of individual difference variables that qualify these results could aid efforts to target treatment approaches appropriately. Laboratory and clinical studies have found greater effectiveness of naltrexone among men and those with familial alcoholism. The present study used multi-level modeling to investigate family history of alcoholism (FHA) based on first-degree relatives and gender as moderators of naltrexone's effects on three drinking outcomes: percentage of days abstinent, drinks per drinking day, and percentage of heavy drinking days. Method: Data were drawn from the COMBINE public data set and included the subsample of participants (n = 603) randomized to receive active medication or placebo plus medical management. Results: We observed a main effect of FHA on drinks per drinking day (B = 2.01, SE = .91, p = .03) such that greater FHA was associated with greater alcohol use per drinking occasion. No other main effects of FHA were observed on drinking outcomes. A significant Naltrexone x Time interaction was observed for percentage of heavy drinking days (B = -1.61, SE = .69, p = .02), consistent with the previously published COMBINE results. No significant Naltrexone x FHA interactions were observed for any of the three outcomes. Gender did not modify these results. Conclusions: Taken together, these results indicate an effect of FHA on drinking behavior but do not support FHA among first-degree relatives as a moderator of naltrexone's efficacy in this sample.

Chen YC; Prescott CA; Walsh D; Patterson DG; Riley BP; Kendler KS et al. Different phenotypic and genotypic presentations in alcohol dependence: Age at onset matters. Journal of Studies on Alcohol and Drugs 72(5): 752-762, 2011. (54 refs.)

Objective: Several theoretical typology models have been proposed to classify alcoholism into more homogeneous subtypes using various criteria, for which age at onset of alcohol dependence is shared across many models. We investigated the evidence for the distinction between early- versus late-onset alcoholism by examining relevant phenotypic and genotypic variables. Method: Data are from 1,248 individuals with alcohol dependence, who were interviewed to collect detailed clinical information. Early versus late onset of alcohol dependence was defined by the age at onset of 22 years. Odds ratio (OR) and Cohen's d were calculated as effect size for comparisons of clinical features between the two groups. We adjusted interviewed age and gender in logistic regression models. Case-control genetic analyses were conducted for the association between HTRIB, SLC6A4, DRD2, and OPR mu 1 genes and subgroups of alcohol dependence using a sample of 530 controls screened for alcohol problems. Results: Early-onset alcoholism exhibited significantly (p < .01) different clinical characteristics from late-onset alcoholism, including higher severity in alcohol dependence symptoms (d = 0.22) and maximum drinking quantity within 24 hours (d = 0.40), more rapid progression from regular drinking to meet alcohol dependence diagnosis (d = 1.73), higher expectancies for alcohol (d = 0.22-0.47), more comorbidity with externalizing disorders (ORs = 2.8-2.9), and greater prevalence of family alcohol use problems (d = 0.26-0.43). In addition, markers in the HTRIB and OPR mu 1 genes showed genetic associations with subgroups of alcohol dependence (ORs = 1.5-2.4). Conclusions: Our findings support that subgroups of alcohol dependence defined by onset age have phenotypic and genetic differences. The early-onset subgroup had more severe features for almost every aspect we examined. Coupled with genetic association findings, age at onset of alcohol dependence may serve as a simple but important clinical marker with implications for future etiological research and intervention.

Claus ED; Ewing SWF; Filbey FM; Sabbineni A; Hutchison KE. Identifying neurobiological phenotypes associated with alcohol use disorder severity. Neuropsychopharmacology 36(10): 2086-2096, 2011. (83 refs.)

Although numerous studies provide general support for the importance of genetic factors in the risk for alcohol use disorders (AUDs), candidate gene and genome-wide studies have yet to identify a set of genetic variations that explain a significant portion of the variance in AUDs. One reason is that alcohol-related phenotypes used in genetic studies are typically based on highly heterogeneous diagnostic categories. Therefore, identifying neurobiological phenotypes related to neuroadaptations that drive the development of AUDs is critical for the future success of genetic and epigenetic studies. One such neurobiological phenotype is the degree to which exposure to alcohol taste cues recruits the basal ganglia, prefrontal cortex, and motor areas, all of which have been shown to have a critical role in addictive behaviors in animal studies. To that end, this study was designed to examine whether cue-elicited responses of these structures are associated with AUD severity in a large sample (n = 326) using voxelwise and functional connectivity measures. Results suggested that alcohol cues significantly activated dorsal striatum, insula/orbitofrontal cortex, anterior cingulate cortex, and ventral tegmental area. AUD severity was moderately correlated with regions involved in incentive salience such as the nucleus accumbens and amygdala, and stronger relationships with precuneus, insula, and dorsal striatum. The findings indicate that AUDs are related to neuroadaptations in these regions and that these measures may represent important neurobiological phenotypes for subsequent genetic studies.

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.

Dahlgren A; Wargelius HL; Berglund KJ; Fahlke C; Blennow K; Zetterberg H et al. Do alcohol-dependent individuals with DRD2 A1 allele have an increased risk of relapse? A pilot study. Alcohol and Alcoholism 46(5): 509-513, 2011. (39 refs.)

Aims: The TaqIA polymorphism of the dopamine D2 receptor (DRD2) gene has been extensively studied in relation to alcoholism, and the TaqI A1 allele appears to be over-represented in alcohol-dependent individuals. In a recent study, this allele has also been associated with a highly increased mortality rate in alcohol-dependent individuals. In the present study, we investigated whether the TaqI A1 allele of the DRD2 gene region was associated with a higher relapse rate in alcohol-dependent individuals. Methods: Adult women (n = 10) and men (n = 40) with a diagnosis of alcohol-dependence were recruited from two Swedish 12-step treatment units for alcoholism. Subjects were genotyped for the TaqIA polymorphism. On average, 1.5 years after the end of the treatment program, subjects were re-interviewed by using the alcohol-related items from the Addiction Severity Index follow-up version. Results: Thirty-three (66%) subjects self-reported relapse and 17 (34%) abstinence during the follow-up period. Thirty-sex percent (18/50) were carriers of the A1 allele of the DRD2 gene region, and 64% (32/50) were non-carriers. Among the carriers of the A1 allele, 89% (16/18) reported relapse in contrast to 53% (17/32) in the non-carriers (P = 0.01; odds ratio = 7.1). Conclusion: The present study is, to our knowledge, the first report of an association between the TaqI A1 allele and a substantially increased relapse rate. It should be emphasized that the number of subjects is relatively small, and this investigation should therefore be considered as a pilot study.

Dick DM. Developmental changes in genetic influences on alcohol use and dependence. Child Development Perspectives 5(4): 223-230, 2011. (57 refs.)

Understanding how genetic influences affect alcohol use and dependence necessitates a developmental perspective. The importance of genetic influences on alcohol use and dependence varies dramatically across development, with environmental influences playing the predominant role early in adolescence and genetic influences assuming increasing importance across adolescence and into young adulthood. In addition, converging lines of evidence suggest that the genetic predisposition to adult alcohol dependence shows heterotypic continuity and is related to conduct problems much earlier in development. It is clear that the genetic susceptibility for alcohol use and dependence unfolds through a complex series of interactions with the environment, with evidence that genetic predispositions influence the selection of environments, such as deviant peers, which further elevate risk for alcohol problems, and that the environment can mitigate or augment the expression of genetic predispositions related to substance use. As genes influencing alcohol dependence are increasingly identified, exciting opportunities exist to integrate these findings with the rich developmental literature in order to map pathways of risk associated with identified genes and their interactions with the environment across development.

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.

Dick DM; Meyers JL; Latendresse SJ; Creemers HE; Lansford JE; Pettit GS et al. CHRM2, parental monitoring, and adolescent externalizing behavior: Evidence for gene-environment interaction. Psychological Science 22(4): 481-489, 2011. (39 refs.)

Psychologists, with their long-standing tradition of studying mechanistic processes, can make important contributions to further characterizing the risk associated with genes identified as influencing risk for psychiatric disorders. We report one such effort with respect to CHRM2, which codes for the cholinergic muscarinic 2 receptor and was of interest originally for its association with alcohol dependence. We tested for association between CHRM2 and prospectively measured externalizing behavior in a longitudinal, community-based sample of adolescents, as well as for moderation of this association by parental monitoring. We found evidence for an interaction in which the association between the genotype and externalizing behavior was stronger in environments with lower parental monitoring. There was also suggestion of a crossover effect, in which the genotype associated with the highest levels of externalizing behavior under low parental monitoring had the lowest levels of externalizing behavior at the extreme high end of parental monitoring. The difficulties involved in distinguishing mechanisms of gene-environment interaction are discussed.

Dick DM; Meyers JL; Rose RJ; Kaprio J; Kendler KS. Measures of current alcohol consumption and problems: Two independent twin studies suggest a complex genetic architecture. Alcoholism: Clinical and Experimental Research 35(12): 2152-2161, 2011. (27 refs.)

Background: Twin studies demonstrate that measures of alcohol consumption (AC) show evidence of genetic influence, suggesting they may be useful in gene identification efforts. The extent to which these phenotypes will be informative in identifying susceptibility genes involved in alcohol dependence depends on the extent to which genetic influences are shared across measures of AC and alcohol problems. Previous studies have demonstrated that AC reported for the period of heaviest lifetime drinking shows a large degree of genetic overlap with alcohol dependence; however, many studies with genetic material assess current AC. Further, there are many different aspects of AC that can be assessed (e.g., frequency of use, quantity of use, and frequency of intoxication). Methods: Here, we use data from 2 large, independent, population-based twin samples, FinnTwin 16 and The Virginia Adult Twin Study of Psychiatric and Substance Use Disorders, to examine the extent to which genetic influences are shared across many different measures of AC and alcohol problems. Results: Genetic correlations across current AC measures and alcohol problems were high across both samples. However, both samples suggest a complex genetic architecture with many different genetic factors influencing various aspects of current AC and problems. Conclusions: These results suggest that careful attention must be paid to the phenotype in efforts to "replicate" genetic effects across samples or combine samples for meta-analyses of genetic effects influencing susceptibility to alcohol-related outcomes.

Du YL; Nie YQ; Li YY; Wan YJY. The association between the SLC6A3 VNTR 9-repeat allele and alcoholism: A meta-analysis. Alcoholism: Clinical and Experimental Research 35(9): 1625-1634, 2011. (52 refs.)

Background: Dopamine transporter gene (SLC6A3) represents a promising candidate involved in the development of alcoholism. This study aimed to explore the association between the 9-repeat allele (A9) of a 40-bp variable number tandem repeat (VNTR) polymorphism in the 3' untranslated region (3' UTR) of the SLC6A3 gene and alcoholism. Methods: The SLC6A3 VNTR was genotyped by PCR in unrelated Mexican Americans including 337 controls and 365 alcoholics. Pearson's chi-square test or Fisher's exact test was used to compare the genotype and allele distribution. Meta-analyses were performed for population-based case-control association studies of the SLC6A3 VNTR polymorphism with alcoholism. Data were analyzed under random effect models with the Comprehensive Meta-analysis (v.2) statistical software package. Results: In Mexican Americans, no significant difference was found in allele and genotype distribution between controls and alcoholics or between controls and alcoholics with alcohol withdrawal seizure (AWS) or delirium tremens (DT) (unadjusted p > 0.05). A total of 13 research articles were included in the meta-analyses. No significant difference of the SLC6A3 VNTR A9 was noted between controls and alcoholics at the genotypic and allelic level when all ethnic populations, only Caucasian populations, or only Asian populations were considered (p > 0.05). Significant associations were observed between SLC6A3 VNTR A9 and alcoholics with AWS or DT at the genotypic as well as allelic level when all ethnic populations or only Caucasian populations were considered (p < 0.05, OR 1.5-2.1). Conclusions: Meta-analyses suggest a possible association between the SLC6A3 VNTR A9 and alcoholic subgroup with AWS or DT.

Du YL; Nie YQ; Li YY; Wan YJY. The association between the SLC6A3 VNTR 9-repeat allele and alcoholism: A meta-analysis. Alcoholism: Clinical and Experimental Research 35(9): 1625-1634, 2011. (52 refs.)

Edwards AC; Aliev F; Bierut LJ; Bucholz KK; Edenberg H; Hesselbrock V et al. Genome-wide association study of comorbid depressive syndrome and alcohol dependence. Psychiatric Genetics 22(1): 31-41, 2012. (79 refs.)

Objective Depression and alcohol dependence (AD) are common psychiatric disorders that often co-occur. Both disorders are genetically influenced, with heritability estimates in the range of 35-60%. In addition, evidence from twin studies suggests that AD and depression are genetically correlated. Herein, we report results from a genome-wide association study of a comorbid phenotype, in which cases meet the Diagnostic and Statistical Manual of Mental Disorders-IV symptom threshold for major depressive symptomatology and the Diagnostic and Statistical Manual of Mental Disorders-IV criteria for AD. Methods Samples (N=467 cases and N=407 controls) were of European-American descent and were genotyped using the Illumina Human 1M BeadChip array. Results Although no single-nucleotide polymorphism (SNP) meets genome-wide significance criteria, we identified 10 markers with P values less than 1 x 10(-5), seven of which are located in known genes, which have not been previously implicated in either disorder. Genes harboring SNPs yielding P values less than 1 x 10(-3) are functionally enriched for a number of gene ontology categories, notably several related to glutamatergic function. Investigation of expression localization using online resources suggests that these genes are expressed across a variety of tissues, including behaviorally relevant brain regions. Genes that have been previously associated with depression, AD, or other addiction-related phenotypes - such as CDH13, CSMD2, GRID1, and HTR1B - were implicated by nominally significant SNPs. Finally, the degree of overlap of significant SNPs between a comorbid phenotype and an AD-only phenotype is modest. Conclusion These results underscore the complex genomic influences on psychiatric phenotypes and suggest that a comorbid phenotype is partially influenced by genetic variants that do not affect AD alone.

Evans SM; Levin FR. Response to alcohol in women: Role of the menstrual cycle and a family history of alcoholism. Drug and Alcohol Dependence 114(1): 18-30, 2011. (86 refs.)

The present study determined whether: (1) the response to alcohol varied as a function of menstrual cycle phase and (2) women with a paternal history of alcoholism (FHP) were less sensitive to the effects of alcohol compared to women without a family history of alcoholism (FHN). The behavioral effects of alcohol (0.00, 0.25, and 0.75 g/kg) were evaluated in 21 FHN and 24 FHP women; each dose was tested during both the midfollicular and late luteal phases of the menstrual cycle. Baseline negative mood was increased during the luteal phase compared to the follicular phase (increased Beck Depression scores and decreased Vigor, Arousal, and Friendly scores). Alcohol increased ratings of Drug Liking and Good Drug Effect more in the luteal phase than the follicular phase. FHP women had greater negative mood during the luteal phase and some of these dysphoric effects were increased by alcohol more in FHP women than FHN women. Alcohol impaired performance, with no group or menstrual cycle differences. However, consistent with previous studies, FHP women were less impaired by alcohol than FHN women on the balance task. These data indicate that (1) the differences in response to alcohol across the menstrual cycle are subtle, although alcohol is liked more during the luteal phase; (2) increases in dysphoric mood during the luteal phase are more pronounced in FHP women compared to FHN women, particularly after alcohol; and (3) the differences observed in response to alcohol between FHP and FHN women are less pronounced than previously shown in men.

Farris SP; Miles MF. Ethanol modulation of gene networks: Implications for alcoholism. (review). Neurobiology of Disease 45(1): 115-121, 2012. (57 refs.)

Alcoholism is a complex disease caused by a confluence of environmental and genetic factors influencing multiple brain pathways to produce a variety of behavioral sequelae, including addiction. Genetic factors contribute to over 50% of the risk for alcoholism and recent evidence points to a large number of genes with small effect sizes as the likely molecular basis for this disease. Recent progress in genomics (microarrays or RNA-Seq) and genetics has led to the identification of a large number of potential candidate genes influencing ethanol behaviors or alcoholism itself. To organize this complex information, investigators have begun to focus on the contribution of gene networks, rather than individual genes, for various ethanol-induced behaviors in animal models or behavioral endophenotypes comprising alcoholism. This chapter reviews some of the methods used for constructing gene networks from genomic data and some of the recent progress made in applying such approaches to the study of the neurobiology of ethanol. We show that rapid technology development in gathering genomic data, together with sophisticated experimental design and a growing collection of analysis tools are producing novel insights for understanding the molecular basis of alcoholism and that such approaches promise new opportunities for therapeutic development.

Gizer IR; Ehlers CL; Vieten C; Seaton-Smith KL; Feiler HS; Lee JV et al. Linkage scan of alcohol dependence in the UCSF Family Alcoholism Study. Drug and Alcohol Dependence 113(2-3): 125-132, 2011. (48 refs.)

Ample data suggest that alcohol dependence represents a heritable condition, and several research groups have performed linkage analysis to identify genomic regions influencing this disorder. In the present study, a genome-wide linkage scan for alcohol dependence was conducted in a community sample of 565 probands and 1080 first-degree relatives recruited through the UCSF Family Alcoholism Study. The Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) was used to derive DSM-IV alcohol dependence diagnoses. Although no loci achieved genome-wide significance (i.e., LOD score > 3.0), several linkage peaks of interest (i.e.. LOD score > 1.0) were identified. When the strict DSM-IV alcohol dependence diagnosis requiring the temporal clustering of symptoms served as the phenotype, linkage peaks were identified on chromosomes 1p36.31-p36.22, 2q37.3, 8q24.3, and 18p11.21-p11.2. When the temporal clustering of symptoms was not required, linkage peaks were again identified on chromosomes 1p36.31-p36.22 and 8q24.3 as well as novel loci on chromosomes 1p22.3, 2p24.3-p24.1, 9p24.1-p23, and 22q12.3-q13.1. Follow-up analyses were conducted by performing linkage analysis for the 12 alcohol dependence symptoms assessed by the SSAGA across the support intervals for the observed linkage peaks. These analyses demonstrated that different collections of symptoms often assessing distinct aspects of alcohol dependence (e.g., uncontrollable drinking and withdrawal vs. tolerance and drinking despite health problems) contributed to each linkage peak and often yielded LOD scores exceeding that reported for the alcohol dependence diagnosis. Such findings provide insight into how specific genomic regions may influence distinct aspects of alcohol dependence.

Goodwin RD; Lipsitz JD; Keyes K; Galea S; Fyer AJ. Family history of alcohol use disorders among adults with panic disorder in the community. Journal of Psychiatric Research 45(8): 1123-1127, 2011. (44 refs.)

Objective: Clinical studies suggest a familial association between panic disorder and alcohol use disorders but this relationship has not been examined in a representative community sample. The objective of this study is to examine the familial association between panic disorder and alcohol use disorders among adults in the community. Method: Data were drawn from the NESARC, a nationally representative sample of over 43,000 adults in the United States. Rates of alcohol use disorders were examined using the family history method in first-degree relatives (FDRs) of adults with panic disorder. Analyses were adjusted for demographics, alcohol use disorders in the proband, and anxiety disorders in the FDRs. Results: First-degree relatives of adults with panic disorder have significantly higher odds of alcohol use disorders, compared with FDRs of adults without panic disorder. These associations persist after adjusting for demographic characteristics, alcohol use disorders in the proband, and anxiety disorders in the FDR's. Conclusions: Consistent with findings from clinical studies, this is the first population-based study to show a familial link between panic disorder and alcohol use disorders. This association appears independent of the influence of comorbidity of alcohol use disorders and anxiety disorders, suggesting a potential familial and/or genetic pathway. Future longitudinal studies will be needed to further understand the mechanism of this observed association.

Gordh AHVS; Brkic S; Soderpalm B. Stress and consumption of alcohol in humans with a Type 1 family history of alcoholism in an experimental laboratory setting. Pharmacology, Biochemistry and Behavior 99(4): 696-703, 2011. (56 refs.)

Background: This paper investigates how stress interacts with alcohol consumption in subjects with a family history of alcoholism. One mechanism for increases in alcohol intake may be that stress alters the subjective effects produced by the drug. Methods: 58 healthy volunteers, divided into two groups of family history positive (FHP) and two groups of family history negative (FHN) participated in two laboratory sessions, in which they performed in one out of two sessions a stress task. Then subjects were allowed to choose up to six additional drinks of ethanol or placebo depending on which session they were randomly assigned to start with. Results: It was found that FHP subjects increased their consumption of alcohol after stress. Conclusions: It is possible that both stress and alcohol specifically exaggerate the feelings of the reward in the FHP individuals in such way that it may increase the likelihood of consuming more alcohol.

Gordh AHVS; Soderpalm B. Healthy subjects with a family history of alcoholism show increased stimulative subjective effects of alcohol. Alcoholism: Clinical and Experimental Research 35(8): 1426-1434, 2011. (55 refs.)

Background: Research has shown that subjects with a family history positive (FHP) of alcoholism are at increased risk for alcoholism and that this group reacts differently to alcohol than family history negative (FHN) subjects. These different levels of sensitivity may make FHP persons more likely to consume alcohol. Here, we tested the hypothesis that subjects FHP for type 1 alcoholism (according to Cloninger) are more sensitive than control subjects to the stimulative, properties of alcohol following a single moderate dose of alcohol. Methods: Fifty-one healthy men and women (22 FHP and 29 FHN) participated in 2 laboratory sessions, in which they consumed a beverage containing ethanol (0.6 g/kg in juice) or placebo (juice alone) in a randomized order. Primary dependent measures were self-report questionnaires of mood states. Results: Subjects with family history of type 1 alcoholism showed increased stimulative responses and an elevated positive mood state after ethanol compared to controls. Conclusions: At this moderate dose, ethanol increased stimulative subjective responses in individuals who were "family history positive." This enhanced sensitivity could motivate to exaggerated drinking and thereby increase the risk for developing alcoholism.

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.

Hakenewerth AM; Millikan RC; Rusyn I; Herring AH; North KE; Barnholtz-Sloan JS et al. Joint Effects of Alcohol Consumption and Polymorphisms in Alcohol and Oxidative stress metabolism genes on risk of head and neck cancer. Cancer Epidemiology, Biomarkers & Prevention 20(11): 2438-2449, 2011. (38 refs.)

Background: Single-nucleotide polymorphisms (SNP) in alcohol metabolism genes are associated with squamous cell carcinoma of the head and neck (SCCHN) and may influence cancer risk in conjunction with alcohol. Genetic variation in the oxidative stress pathway may impact the carcinogenic effect of reactive oxygen species produced by ethanol metabolism. We hypothesized that alcohol interacts with these pathways to affect SCCHN incidence. Methods: Interview and genotyping data for 64 SNPs were obtained from 2,552 European-and African-American subjects (1,227 cases and 1,325 controls) from the Carolina Head and Neck Cancer Epidemiology Study, a population-based case-control study of SCCHN conducted in North Carolina from 2002 to 2006. We estimated ORs and 95% confidence intervals (CI) for SNPs and haplotypes, adjusting for age, sex, race, and duration of cigarette smoking. P values were adjusted for multiple testing using Bonferroni correction. Results: Two SNPs were associated with SCCHN risk: ADH1B rs1229984Aallele (OR = 0.7; 95% CI, 0.6-0.9) and ALDH2 rs2238151 C allele (OR = 1.2; 95% CI, 1.1-1.4). Three were associated with subsite tumors: ADH1B rs17028834 C allele (larynx, OR = 1.5; 95% CI, 1.1-2.0), SOD2 rs4342445 A allele (oral cavity, OR = 1.3; 95% CI, 1.1-1.6), and SOD2 rs5746134 T allele (hypopharynx, OR = 2.1; 95% CI, 1.2-3.7). Four SNPs in alcohol metabolism genes interacted additively with alcohol consumption: ALDH2 rs2238151, ADH1B rs1159918, ADH7 rs1154460, and CYP2E1 rs2249695. No alcohol interactions were found for oxidative stress SNPs. Conclusions and Impact: Previously unreported associations of SNPs in ALDH2, CYP2E1, GPX2, SOD1, and SOD2 with SCCHN and subsite tumors provide evidence that alterations in alcohol and oxidative stress pathways influence SCCHN carcinogenesis and warrant further investigation.

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.

Heath AC; Whitfield JB; Martin NG; Pergadia ML; Goate AM; Lind PA et al. A quantitative-trait genome-wide association study of alcoholism risk in the community: Findings and implications. Biological Psychiatry 70(6): 513-518, 2011. (48 refs.)

Background: Given moderately strong genetic contributions to variation in alcoholism and heaviness of drinking (50% to 60% heritability) with high correlation of genetic influences, we have conducted a quantitative trait genome-wide association study (GWAS) for phenotypes related to alcohol use and dependence. Methods: Diagnostic interview and blood/buccal samples were obtained from sibships ascertained through the Australian Twin Registry. Genome-wide single nucleotide polymorphism (SNP) genotyping was performed with 8754 individuals (2062 alcohol-dependent cases) selected for informativeness for alcohol use disorder and associated quantitative traits. Family-based association tests were performed for alcohol dependence, dependence factor score, and heaviness of drinking factor score, with confirmatory case-population control comparisons using an unassessed population control series of 3393 Australians with genome-wide SNP data. Results: No findings reached genome-wide significance (p = 8.4 x 10(-8) for this study), with lowest p value for primary phenotypes of 1.2 x 10(-7). Convergent findings for quantitative consumption and diagnostic and quantitative dependence measures suggest possible roles for a transmembrane protein gene (TMEM108) and for ANKS1A. The major finding, however, was small effect sizes estimated for individual SNPs, suggesting that hundreds of genetic variants make modest contributions (1/4% of variance or less) to alcohol dependence risk. Conclusions: We conclude that 1) meta-analyses of consumption data may contribute usefully to gene discovery; 2) translation of human alcoholism GWAS results to drug discovery or clinically useful prediction of risk will be challenging; and 3) through accumulation across studies, GWAS data may become valuable for improved genetic risk differentiation in research in biological psychiatry (e. g., prospective high-risk or resilience studies).

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; Wall TL; Otto JM; Liang TB et al. Evaluating a cognitive model of ALDH2 and drinking behavior. Alcoholism: Clinical and Experimental Research 35(1): 91-98, 2011. (54 refs.)

Background: Despite evidence for genetic influences on alcohol use and alcohol-related cognitions, genetic factors and endophenotypes are rarely incorporated in cognitive models of drinking behavior. This study evaluated a model of ALDH2 and drinking behavior stipulating cognitive factors and alcohol sensitivity as accounting for genetic influences on drinking outcomes. Methods: Participants were Asian-American young adults (n = 171) who completed measures of alcohol cognitions (drinking motives, drinking refusal self-efficacy, and alcohol expectancies), alcohol sensitivity, drinking behavior, and alcohol-related problems as part of a prospective study. Structural equation modeling (SEM) evaluated a model of drinking behavior that stipulated indirect effects of ALDH2 on drinking outcomes through cognitive variables and alcohol sensitivity. Results: The full model provided an adequate fit to the observed data, with the measurement model explaining 63% of the variance in baseline heavy drinking and 50% of the variance in alcohol-related problems at follow-up. Associations of ALDH2 with cognitive factors and alcohol sensitivity were significant, whereas the association of ALDH2 with drinking was not significant with these factors included in the model. Mediation tests indicated significant indirect effects of ALDH2 through drinking motives, drinking refusal self-efficacy, and alcohol sensitivity. Conclusions: Results are consistent with the perspective that genetic influences on drinking behavior can be partly explained by learning mechanisms and implicate cognitive factors as important for characterizing associations of ALDH2 with drinking.

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.

Herman AI; Conner TS; Anton RF; Gelernter J; Kranzler HR; Covault J. Variation in the gene encoding the serotonin transporter is associated with a measure of sociopathy in alcoholics. Addiction Biology 16(1): 124-132, 2011. (58 refs.)

The present study examined the association between a measure of sociopathy and 5-HTTLPR genotype in a sample of individuals from Project MATCH, a multi-center alcohol treatment trial. 5-HTTLPR, an insertion-deletion polymorphism in SLC6A4, the gene encoding the serotonin transporter protein, results in functionally distinct long (L) and short (S) alleles. The S allele has been associated with a variety of psychiatric disorders and symptoms including alcohol dependence, but it is unknown whether 5-HTTLPR increases the risk for co-morbid sociopathy among those with alcohol dependence. Eight hundred sixty-two subjects diagnosed with alcohol dependence completed the California Psychological Inventory, a psychological assessment that includes a measure of socialization, which was used as a proxy measure of sociopathy. Subjects were genotyped for the insertion-deletion polymorphism, as well as a single nucleotide polymorphism (A -> G) that is located in the inserted region. Regression analysis revealed that after controlling for age, which was negatively related to socialization score, 5-HTTLPR genotype interacted with sex to determine socialization score (P < 0.001). Males with the L'L' genotype (i.e. those homozygous for the L-A allele) had lower socialization scores (i.e. greater sociopathy) than males who were carriers of the S' allele (P = 0.03). In contrast, women with the S'S' genotype had lower socialization scores than women with two L' alleles (P = 0.002) and tended to have lower Socialization Index of the California Psychological Inventory scores than women with one copy of the L' allele (P = 0.07). Among individuals with alcohol use disorders, the tri-allelic 5-HTTLPR polymorphism had opposite effects on socialization scores in men than women. The basis for this finding is unknown, but it may have implications for sub-typing alcoholics.

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.

Hill SY; Tessner KD; McDermott MD. Psychopathology in offspring from families of alcohol dependent female probands: A prospective study. Journal of Psychiatric Research 45(3): 285-294, 2011. (57 refs.)

Background: Despite the importance of understanding the long-term outcome for children of alcohol dependent (AD) women, the available literature is largely based on offspring of AD fathers and few have utilized prospective designs that include child, adolescent and young adult assessments. Multiplex AD families in which multiple cases of AD are present provide an ideal setting for understanding developmental variants of the adult phenotype. Method: Offspring from multiplex AD families identified through the mother or control families were evaluated multiple times during childhood and followed to young adulthood. Familial risk status and the presence of specific child/adolescent disorders were used as predictors of substance use disorder outcome by young adulthood. Results: Offspring who were members of maternal multiplex families had elevated rates of child and young adulthood disorders. High risk offspring of alcohol dependent women were at increased risk for externalizing (Conduct Disorder and ADHD) and internalizing disorders (Major Depressive Disorder (MDD) and Anxiety Disorders). By young adulthood, offspring from these multiplex families had significantly greater odds of developing alcohol abuse or dependence (odds ratio [OR] = 3.63 [CI 1.36-9.641) and drug abuse or dependence (OR = 4.23 [CI 1.73-10.32]). The prospective design of the study revealed that specific childhood disorders (Conduct Disorder, ADHD, MOD) increased the odds of subsequent development of substance use disorder (SLID). Conclusions: Multiplex familial risk for alcohol dependence is a significant predictor of substance use disorders by young adulthood. Familial risk and an earlier childhood disorder may set the stage for later development of SLID.

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.

Islami F; Fedirko V; Tramacere I; Bagnardi V; Jenab M; Scotti L et al. Alcohol drinking and esophageal squamous cell carcinoma with focus on light-drinkers and never-smokers: A systematic review and meta-analysis. International Journal of Cancer 129(10): 2473-2484, 2011. (70 refs.)

Quantification of the association between alcohol drinking and risk of esophageal squamous cell carcinoma (ESCC) is an open issue, particularly among light alcohol drinkers, never-smokers, and Asian populations, in which some high-risk polymorphisms in alcohol metabolizing genes are more prevalent. To address these issues, we conducted a systematic review and meta-analysis using 40 case-control and 13 cohort studies that reported on the risk associated with alcohol drinking for at least three levels of consumption. In studies adjusted for age, sex, and tobacco smoking, the relative risk (RR) and 95% confidence interval (CI) for the association between light alcohol drinking (<= 12.5 g/d) and risk of ESCC was 1.38 (1.14-1.67). The association was slightly stronger in Asian countries than in other populations. The adjusted RRs (95% CIs) were 2.62 (2.07-3.31) for moderate drinking (>12.5-<50 g/d) and 5.54 (3.92-7.28) for high alcohol intake (>= 50 g/d); the RRs were slightly higher in non-Asian populations. In prospective studies, the RR (95% CI) was 1.35 (0.92-1.98) for light, 2.15 (1.55-2.98) for moderate, and 3.35 (2.06-5.46) for high alcohol intakes; light drinking showed an association with ESCC in Asia (five studies) but not in other regions (three studies). Among never-smokers (nine studies), the RR (95% CI) was 0.74 (0.47-1.16) for light, 1.54 (1.09-2.17) for moderate, and 3.09 (1.75-5.46) for high intakes. This meta-analysis further corroborates the association of moderate and high alcohol intake with risk of ESCC and provides risk estimates based on multiple prospective studies. Light alcohol intake appears to be associated to ESCC mainly in studies in Asia, which suggests a possible role of genetic susceptibility factors.

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.

Johnson BA; Ait-Daoud N; Seneviratne C; Roache JD; Javors MA; Wang XQ et al. Pharmacogenetic approach at the serotonin transporter gene as a method of reducing the severity of alcohol drinking. American Journal of Psychiatry 168(3): 265-275, 2011. (55 refs.)

Objective: Severe drinking can cause serious morbidity and death. Because the serotonin transporter (5-HTT) is an important regulator of neuronal 5-HT function, allelic differences at that gene may modulate the severity of alcohol consumption and predict therapeutic response to the 5-HT3 receptor antagonist, ondansetron. Method: The authors randomized 283 alcoholics by genotype in the 5'-regulatory region of the 5-HTT gene (LL/LS/SS), with additional genotyping for another functional single-nucleotide polymorphism (T/G), rs1042173, in the 3'-untranslated region, in a double-blind controlled trial. Participants received either ondansetron (4 mu g/kg twice daily) or placebo for 11 weeks, plus standardized cognitive-behavioral therapy. Results: Individuals with the LL genotype who received ondansetron had a lower mean number of drinks per drinking day (-1.62) and a higher percentage of days abstinent (11.27%) than those who received placebo. Among ondansetron recipients, the number of drinks per drinking day was lower (-1.53) and the percentage of days abstinent higher (9.73%) in LL compared with LS/SS individuals. LL individuals in the ondansetron group also had a lower number of drinks per drinking day (-1.45) and a higher percentage of days abstinent (9.65%) than all other genotype and treatment groups combined. For both number of drinks per drinking day and percentage of days abstinent, 5'-HTTLPR and rs1042173 variants interacted significantly. LL/TT individuals in the ondansetron group had a lower number of drinks per drinking day (-2.63) and a higher percentage of days abstinent (16.99%) than all other genotype and treatment groups combined. Conclusions: The authors propose a new pharmacogenetic approach using ondansetron to treat severe drinking and improve abstinence in alcoholics.

Karahanian E; Quintanilla ME; Tampier L; Rivera-Meza M; Bustamante D; Gonzalez-Lira V et al. Ethanol as a prodrug: Brain metabolism of ethanol mediates its reinforcing effects. Alcoholism: Clinical and Experimental Research 35(4): 606-612, 2011. (39 refs.)

Background: While the molecular entity responsible for the rewarding effects of virtually all drugs of abuse is known, that for ethanol remains uncertain. Some lines of evidence suggest that the rewarding effects of alcohol are mediated not by ethanol per se but by acetaldehyde generated by catalase in the brain. However, the lack of specific inhibitors of catalase has not allowed strong conclusions to be drawn about its role on the rewarding properties of ethanol. The present studies determined the effect on voluntary alcohol consumption of two gene vectors, one designed to inhibit catalase synthesis and one designed to synthesize alcohol dehydrogenase (ADH), to respectively inhibit or increase brain acetaldehyde synthesis. Methods: The lentiviral vectors, which incorporate the genes they carry into the cell genome, were (i) one encoding a shRNA anticatalase synthesis and (ii) one encoding alcohol dehydrogenase (rADH1). These were stereotaxically microinjected into the brain ventral tegmental area (VTA) of Wistar-derived rats bred for generations for their high alcohol preference (UChB), which were allowed access to an ethanol solution and water. Results: Microinjection into the VTA of the lentiviral vector encoding the anticatalase shRNA virtually abolished (-94%p < 0.001) the voluntary consumption of alcohol by the rats. Conversely, injection into the VTA of the lentiviral vector coding for ADH greatly stimulated (2 to 3 fold p < 0.001) their voluntary ethanol consumption. Conclusions: The study strongly suggests that to generate reward and reinforcement, ethanol must be metabolized into acetaldehyde in the brain. Data suggest novel targets for interventions aimed at reducing chronic alcohol intake.

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.)

Kebir O; Gorsane MA; Blecha L; Krebs MO; Michel R; Benyamina A. Associations of inflammation genes with alcohol dependence/abuwe: A systematic review and meta-analysis. (review). European Addiction Research 17(3): 154-163, 2011. (45 refs.)

The aim of the present work was to systematically review all association studies of inflammation genes with alcohol dependence/alcohol abuse (AD/AA) 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 AD/AA cases versus controls. Data reported in at least three published studies were available for four genetic polymorphisms [TNF-? -238 (rs361525, G/A); TNF-? -308 (rs1800629, G/A); IL-1RA (VNTR [86 bp]_n); IL-10 -592 (rs1800896, C/A)]. In total, nine meta-analyses were performed. Of these, only the TNF-? -238 polymorphism showed a significant association with AD/AA (OR = 1.36, 95% CI: 1.05-1.76). This risk remained significant and increased slightly when we considered only patients with advanced alcohol-related liver disease (AALD) (OR = 1.5, 95% CI: 1.13-1.98) but not when we considered only patients without AALD (OR = 1.08, 95% CI: 0.5-2.35). Sensitivity analysis showed that this genetic association is derived from the AALD phenotype rather than from AD. Our approach is limited by our phenotype definition; some studies included chronic heavy drinkers (minimal daily consumption of 80 g for a minimal duration of 10 years) but without a standardized psychiatric assessment.

Kendler KS; Gardner C; Dick DM. Predicting alcohol consumption in adolescence from alcohol-specific and general externalizing genetic risk factors, key environmental exposures and their interaction. Psychological Medicine 41(7): 1507-1516, 2011. (50 refs.)

Background. Alcohol consumption is influenced by specific genetic risk factors for alcohol use disorders (AUDs), non-specific genetic risk factors for externalizing behaviors and various environmental experiences. We have limited knowledge of how these risk factors inter-relate through development. Method. Retrospective assessments in 1796 adult male twins using a life history calendar of key environmental exposures and alcohol consumption from early adolescence to mid-adulthood. Analysis by linear mixed models. Results. The importance of non-specific genetic risk factors on maximal alcohol consumption rose rapidly in early to mid-adolescence, peaked at ages 15-17 years and then declined slowly. Alcohol-specific genetic risk factors increased slowly in influence through mid-adulthood. We detected robust evidence for environmental moderation of genetic effects on alcohol consumption that was more pronounced in early and mid-adolescence than in later periods. Alcohol availability, peer deviance and low prosocial behaviors showing the strongest moderation effects. More interactions with environmental risk factors were seen for the non-specific externalizing disorder risk than for specific genetic risk for AUDs. Conclusions. The impact of specific and non-specific genetic influences on alcohol consumption have different development trajectories. Genetic effects on alcohol use are more pronounced when social constraints are minimized (e. g. low prosocial behaviors or parental monitoring) or when the environment permits easy access to alcohol and/or encourages its use (e. g. high alcohol availability or peer deviance). Gene-environment interactions influencing alcohol intake may be more robust at younger ages, indicating greater plasticity of genetic influences early in the development of drinking patterns.

Kendler KS; Gardner CO; Prescott CA. Toward a comprehensive developmental model for alcohol use disorders in men. Twin Research and Human Genetics 14(1): 1-15, 2011. (84 refs.)

The multiple risk factors for alcohol use (AU) and alcohol use disorders (AUDs) are interrelated through poorly understood pathways, many of which begin in childhood. In this report, the authors seek to develop an empirical, broad-based developmental model for the etiology of AU and AUDs in men. We assessed 15 risk factors in four developmental tiers in 1,794 adult male twins from the Virginia population based twin registry. The best fitting model explained 39% of the variance in late adolescent AU, and 30% of the liability to lifetime symptoms of AUD. AU and AUDs can be best understood as arising from the action and interaction of two pathways reflecting externalizing genetic/temperamental and familial/social factors. Peer group deviance was important in each pathway. Internalizing symptoms played a more minor role. Familial/social factors were especially important influences on AU, while genetic/temperamental factors were more critical for AUDs. We conclude that AU and AUDs in men are complex traits influenced by genetic, family, temperamental, and social factors, acting and interacting over developmental time.

Kertes DA; Kalsi G; Prescott CA; Kuo PH; Patterson DG; Walsh D et al. Neurotransmitter and neuromodulator genes associated with a history of depressive symptoms in individuals with alcohol dependence. Alcoholism: Clinical and Experimental Research 35(3): 496-505, 2011. (62 refs.)

Background: Depressive symptoms are common among individuals with alcohol use disorders and impact treatment outcome. Substantial overlap exists among the neurobiological systems proposed in the pathophysiology of depressive and alcohol use disorders; however, specific genetic effects contributing to risk for depressive comorbidity remain poorly understood. Methods: This study examines the association of depressive symptom scores for lifetime depression (the sum of DSM-IV major depression co-endorsed criteria for lifetime depression) with markers in 120 candidate genes in 554 alcohol-dependent individuals. The candidate genes code for molecules involved in dopamine, serotonin, glutamate, gamma-aminobutyric acid (GABA), and opioid neurotransmission, cell signaling, pharmacokinetics, stress biology, and behavioral control. Analyses were conducted at the single marker level with experimentwise permutation to control for multiple testing. Results: Results revealed nominal associations for markers in 20 genes. Following experimentwise permutation, markers in the corticotropin-releasing hormone-binding protein (CRHBP) the mu-opioid receptor (OPRM1) and the beta 1 subunit of GABA A (GABA(A)) receptors (GABRB1) met or exceeded the significance threshold. None of the markers associated with depressive symptom scores were significantly associated with alcohol dependence symptom scores. Conclusion: These findings suggest potential risk genes for depressive symptoms in alcohol-dependent individuals.

Koskinen SM; Ahveninen J; Kujala T; Kaprio J; O'Donnell BF; Osipova D et al. A longitudinal twin study of effects of adolescent alcohol abuse on the neurophysiology of attention and orienting. Alcoholism: Clinical and Experimental Research 35(7): 1339-1350, 2011. (66 refs.)

Background: Long-term functional brain effects of adolescent alcohol abuse remain uncertain, partially because of difficulties in distinguishing inherited deficits from neuronal effects of ethanol and by confounds associated with alcohol abuse, especially nicotine exposure. We conducted a longitudinal twin study to determine neurocognitive effects of adolescent alcohol abuse, as measured with the auditory event-related potential (ERP) component P3, a putative marker of genetic vulnerability to alcoholism. Methods: Twin pairs (N = 177; 150 selected for intrapair concordance/discordance for alcohol-related problems at age 18 1/2) were recruited from ongoing studies of twins born 1975-1979 in Finland. Alcohol and tobacco use were assessed with questionnaires at ages 16, 17, 18 1/2, and similar to 25, and by a structured psychiatric interview concurrent with the ERP testing at mean age 25.8. During ERP recordings, subjects were instructed to detect target tones within a train of frequent "standards" and to ignore occasional "novel" sounds. To distinguish familial factors from ethanol effects, ERP and self-reported alcohol use measures were incorporated into hierarchical multiple regression (HMR) analysis, and intrapair differences in ERP were associated with intrapair differences in alcohol variables. Results: Novel-sound P3 amplitude correlated negatively with self-reported alcohol use in both between- and within-family analyses. No similar effect was observed for target-tone P3. HMR results suggest that twins' similarity for novel-sound P3 amplitude is modulated by their alcohol use, and this effect of alcohol use is influenced by genetic factors. Conclusions: Our results, from a large sample of twins selected from a population-based registry for pairwise concordance/discordance for alcohol problems at 18 1/2, demonstrate that adolescent alcohol abuse is associated with subtle neurophysiological changes in attention and orienting. The changes are reflected in decreased novel-sound P3 amplitude and may be modified by genetic factors.

Landgren S; Berglund K; Jerlhag E; Fahlke C; Balldin J; Berggren U et al. Reward-related genes and personality traits in alcohol-dependent individuals: A pilot case control study. Neuropsychobiology 64(1): 38- 46, 2011. (52 refs.)

Components of the brain reward system, i.e. the mesolimbic dopamine, laterodorsal cholinergic and ghrelin signaling systems, have been implicated in alcohol reward in preclinical studies. Genetic variants of these systems have previously been linked to alcohol dependence. Here, we genotyped 31 single nucleotide polymorphisms (SNPs): 1 SNP in the dopamine D 2 receptor (DRD2) gene, 20 SNPs in 5 different nicotinic acetylcholine receptor subunit (CHRN*) genes, and 10 SNPs in the genes encoding pro-ghrelin (GHRL) and its receptor (GHSR), in a pilot study of type 1 alcoholics (n = 84) and healthy controls (n = 32). These individuals were characterized using the Temperament and Character Inventory. None of the SNPs were associated with risk of alcohol dependence in this population. The GG genotype of SNP rs13261190 in the CHRNB3 was associated with increased novelty seeking, while SNPs of the ghrelin signaling system were associated with decreased self-directedness (AA of rs495225, GHSR) and alterations in self-transcendence (AA of both rs42451 and rs35680, GHRL). In conclusion, this pilot study suggests that reward-related genes are associated with altered personality scores in type 1 alcohol dependence, which warrants future studies of these associations in larger study samples.

Latvala A; Dick DM; Tuulio-Henriksson A; Suvisaari J; Viken RJ; Rose RJ et al. Genetic correlation and gene-environment interaction between alcohol problems and educational level in young adulthood. Journal of Studies on Alcohol and Drugs 72(2): 210-220, 2011. (57 refs.)

Objective: A lower level of education often co-occurs with alcohol problems, but factors underlying this co-occurrence are not well understood. Specifically, whether these outcomes share part of their underlying genetic influences has not been widely studied. Educationational level also reflects various environmental influences that may moderate the genetic etiology of alcohol problems, but gene environment interactions between educational attainment and alcohol problems are unknown. Method: We studied the two nonmutually exclusive possibilities of common genetic influences and gene environment interaction between alcohol problems and low education using a population-based sample (n = 4,858) of Finnish young adult twins (M-age = 24.5 years, range: 22.8-28.6 years). Alcohol problems were assessed with the Rutgers Alcohol Problem Index and self-reported maximum number of drinks consumed in a 24-hour period. Years of education, based on completed and ongoing studies, represented educational level. Results: Educationational level was inversely associated with alcohol problems in young adulthood, and this association was most parsimoniously explained by overlapping genetic influences. Independent of this co-occurrence, higher education was associated with increased relative importance of genetic influences on alcohol problems, whereas environmental factors had a greater effect among twins with lower education. Conclusions: Our findings suggest a complex relationship between educational level and alcohol problems in young adulthood. Lower education is related to higher levels of alcohol problems, and this co-occurrence is influenced by genetic factors affecting both phenotypes. In addition, educational level moderates the importance of genetic and environmental influences on alcohol problems, possibly reflecting differences in social-control mechanisms related to educational level.

Latvala A; Tuulio-Henriksson A; Dick DM; Vuoksimaa E; Viken RJ; Suvisaari J et al. Genetic origins of the association between verbal ability and alcohol dependence symptoms in young adulthood. Psychological Medicine 41(3): 641-651, 2011. (53 refs.)

Background. Cognitive deficits in alcohol dependence (AD) have been observed, poorer verbal ability being among the most consistent findings. Genetic factors influence both cognitive ability and AD, but whether these influences overlap is not known. Method. A subset of 602 monozygotic (MZ) and dizygotic (DZ) twins from FinnTwin16, a population-based study of Finnish twins, was used to study the associations of verbal ability with DSM-III-R diagnosis and symptoms of AD, the maximum number of drinks consumed in a 24-h period, and the Rutgers Alcohol Problem Index (RAPI) scores. These twins, most of them selected for within-pair discordance or concordance for their RAPT scores at age 18.5 years, were studied with neuropsychological tests and interviewed with the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) in young adulthood (mean age 26.2 years, range 23-30 years). Results. All alcohol problem measures were associated with lower scores on the Vocabulary subtest of the Wechsler Adult Intelligence Scale - Revised (WAIS-R), a measure of verbal ability. In bivariate genetic models, Vocabulary and the alcohol problem measures had moderate heritabilities (0.54-0.72), and their covariation could be explained by correlated genetic influences (genetic correlations -0.20 to -0.31). Conclusions. Poorer verbal ability and AD have partly overlapping biological etiology. The genetic and environmental influences on the development of cognitive abilities, alcohol problems and risk factors for AD should be studied further with prospective longitudinal designs.

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 DW; Zhao HY; Gelernter J. Strong association of the alcohol dehydrogenase 1B gene (ADH1B) with alcohol dependence and alcohol-induced medical diseases. Biological Psychiatry 70(6): 504-512, 2011. (111 refs.)

Background: The alcohol dehydrogenase 1B gene (ADH1B) is hypothesized to affect predisposition to alcohol dependence (AD) and abuse. A variant of the ADH1B gene (rs1229984 or Arg48His; previously referred to as Arg [*1] and His [*1]) has been reported to be associated with reduced rates of alcohol and drug dependence. Different studies have produced inconclusive results regarding association between rs1229984 (or rs2066702) and substance dependence. Methods: Using the cumulative association study literature from the past 21 years from both English-and Chinese-language publications, this meta-analysis seeks to clarify the contradictory findings and to examine whether the aggregate data provide new evidence of significant association. Results: The results, based on a large sample size (9638 cases and 9517 controls), suggested strong associations with alcohol dependence and abuse as well as alcohol-induced liver diseases, with an allelic (Arg vs. His) p value being 1 x 10(-36) and odds ratio (OR) (95% confidence intervals [CI]) 2.06 (1.84-2.31) under the random effects model. The dominant and recessive models produced larger ORs of 2.17 and 3.05, respectively. When more stringent criteria and subgroup analyses were imposed, the associations remained consistent and were strongest in various Asian groups (allelic p = 7 x 10(-42) and OR (95% CI) = 2.24 [1.99-2.51] with ORs of 2.16 and 4.11 for dominant and recessive models, respectively). Conclusions: Our findings provide further strong evidence for the involvement of the ADH1B gene in the pathogenesis of alcohol dependence and abuse as well as for some alcohol-induced medical diseases in the multiple ethnic populations-in particular, certain Asian populations.

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.

Littlefield AK; Agrawal A; Ellingson JM; Kristjansson S; Madden PAF; Bucholz KK et al. Does variance in drinking motives explain the genetic overlap between personality and alcohol use disorder symptoms? A twin study of young women. Alcoholism: Clinical and Experimental Research 35(12): 2242-2250, 2011. (0 refs.)

Background: Genetic risk for alcohol dependence has been shown to overlap with genetic factors contributing to variation in dimensions of personality. Although drinking motives have been posited as important mediators of the alcoholpersonality relation, the extent to which the genetic covariance between alcohol use disorder (AUD) symptoms (i.e., abuse and dependence criteria) and personality is explained by genetic factors contributing to variation in drinking motives remains unclear. Methods: Using data from 2,904 young adult female twins, the phenotypic and genetic associations between personality dimensions (constraint [measured by the Multidimensional Personality Questionnaire; Tellegen A, 1982 unpublished data], conscientiousness, neuroticism, and agreeableness [measured by the NEO-PI; Costa and McCrae, 1985]), internal drinking motives (enhancement and coping motives [measured by the Drinking Motive Questionnaire; Cooper, 1994]), and AUD symptoms were tested. Results: Significant genetic associations were found between all personality measures and AUD symptoms. Coping motives showed significant genetic overlap with AUD symptoms and most personality measures, whereas enhancement motives were not significantly heritable. Adjusting for coping motives, genetic correlations between AUD symptoms and traits of neuroticism and agreeableness were no longer statistically significant. Conclusions: Findings suggest that genetic variation in drinking to cope might account for a considerable proportion of the genetic covariance between specific personality dimensions and AUD symptoms.

Liu JX; Zhou ZF; Hodgkinson CA; Yuan QP; Shen PH; Mulligan CJ et al. Haplotype-based study of the association of alcohol-metabolizing genes with alcohol dependence in four independent populations. Alcoholism: Clinical and Experimental Research 35(2): 304-316, 2011. (63 refs.)

Background: Ethanol is metabolized by 2 rate-limiting reactions: alcohol dehydrogenases (ADH) convert ethanol to acetaldehyde that is subsequently metabolized to acetate by aldehyde dehydrogenases (ALDH). Approximately 50% of East Asians have genetic variants that significantly impair this pathway and influence alcohol dependence (AD) vulnerability. We investigated whether variation in alcohol metabolism genes might alter the AD risk in four non-East Asian populations by performing systematic haplotype association analyses to maximize the chances of capturing functional variation. Methods: Haplotype-tagging SNPs were genotyped using the Illumina GoldenGate platform. Genotypes were available for 40 SNPs across the ADH genes cluster and 24 SNPs across the two ALDH genes in four diverse samples that included cases (lifetime AD) and controls (no Axis 1 disorders). The case control sample sizes were the following: Finnish Caucasians: 232, 194; African Americans: 267, 422; Plains American Indians: 226, 110; and Southwestern American (SW) Indians: 317, 72. Results: In all four populations, as well as HapMap populations, 5 haplotype blocks were identified across the ADH gene cluster: (i) ADH5-ADH4; (ii) ADH6-ADH1A-ADH1B; (iii) ADH1C; (iv) intergenic; (v) ADH7. The ALDH1A1 gene was defined by 4 blocks and ALDH2 by 1 block. No haplotype or SNP association results were significant after correction for multiple comparisons; however, several results, particularly for ALDH1A1 and ADH4, replicated earlier findings. There was an ALDH1A1 block 1 and 2 (extending from intron 5 to the 3' UTR) yin yang haplotype (haplotypes that have opposite allelic configuration) association with AD in the Finns driven by SNPs rs3764435 and rs2303317, respectively, and an ALDH1A1 block 3 (including the promoter region) yin yang haplotype association in SW Indians driven by 5 SNPs, all in allelic identity. The ADH4 SNP rs3762894 was associated with AD in Plains Indians. Conclusions: The systematic evaluation of alcohol-metabolizing genes in four non-East Asian populations has shown only modest associations with AD, largely for ALDH1A1 and ADH4. A concentration of signals for AD with ALDH1A1 yin yang haplotypes in several populations warrants further study.

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.

Luczak SE; Pandika D; Shea SH; Eng MY; Liang TB; Wall TL. ALDH2 and ADH1B interactions in retrospective reports of low-dose reactions and initial sensitivity to alcohol in Asian American college students. Alcoholism: Clinical and Experimental Research 35(7): 1238-1245, 2011. (52 refs.)

Background: A mechanistic model has been proposed for how alcohol-metabolizing gene variants protect individuals from the development of alcohol use disorders, with heightened sensitivity to alcohol being an early step (endophenotype) in this model. This study was designed to determine whether possession of 2 alcohol-metabolizing genes variations, the aldehyde dehydrogenase ALDH2*2 allele and the alcohol dehydrogenase ADH1B*2 allele, was associated with self-reported sensitivity to alcohol at low doses and at initial use. Methods: Asian-American college students (N = 784) of Chinese and Korean descent were genotyped at the ALDH2 and ADH1B loci and assessed for lifetime alcohol symptoms following 1 or 2 drinks and level of response to alcohol during the first 5 lifetime drinking episodes. Results: Participants who had an ALDH2*2 allele were more likely to report experiencing all 6 low-dose symptoms and having heightened initial response to alcohol. An interaction was found between ALDH2*2 and ADH1B*2, with ADH1B*2 being associated with heightened self-reported sensitivity to alcohol only in individuals who also possessed 1 ALDH2*2 allele. Conclusions: These findings suggest the effects of ADH1B*2 may be felt more strongly in Asians who already have some heightened sensitivity to alcohol from possessing 1 ALDH2*2 allele, but who are not too sensitized to alcohol from possessing 2 ALDH2*2 alleles. These results offer additional insight into the discrepant findings that have been reported in the literature for the role of ADH1B*2 in response to alcohol and the development of alcohol-related problems.

Lydall GJ; Bass NJ; McQuillin A; Lawrence J; Anjorin A; Kandaswamy R; Pereira A et al. Confirmation of prior evidence of genetic susceptibility to alcoholism in a genome-wide association study of comorbid alcoholism and bipolar disorder. Psychiatric Genetics 21(6): 294-306, 2011. (123 refs.)

Objectives: Alcoholism and affective disorders are both strongly comorbid and heritable. We have investigated the genetic comorbidity between bipolar affective disorder and alcoholism. Methods: A genome-wide allelic association study of 506 patients from the University College London bipolar disorder case-control sample and 510 ancestrally matched supernormal controls. One hundred forty-three of the bipolar patients fulfilled the Research Diagnostic Criteria diagnosis of alcoholism. A total of 372 193 single nucleotide polymorphisms (SNPs) were genotyped. Genes previously shown to be associated with alcoholism and addiction phenotypes were then tested for association in the bipolar alcoholic sample using gene-wise permutation tests of all SNPs genotyped within a 50-kb region flanking each gene. Results: Several central nervous system genes showed significant (P<0.05) gene-wise evidence of association with bipolar alcoholism. The genes implicated, which replicated genes previously shown to be associated with alcoholism were: cadherin 11, collagen type 11 alpha 2, neuromedin U receptor 2, exportin7, and semaphorin-associated protein 5A. The SNPs most strongly implicated in bipolar alcoholism, but, which did not meet conventional genome-wide significance criteria were the insulin-like growth factor-binding protein 7, carboxypeptidase O, cerebellin 2, and the cadherin 12 genes. Conclusion: We have confirmed the role of some genes previously shown to be associated with alcoholism in the comorbid bipolar alcoholism subgroup. In this subgroup, bipolar disorder may lower the threshold for the phenotypic expression of these alcoholism susceptibility genes. We also show that some genes may independently increase susceptibility to affective disorder and alcoholism.

Olvera RL; Bearden CE; Velligan DI; Almasy L; Carless MA; Curran JE et al. Common genetic influences on depression, alcohol, and substance use disorders in Mexican-American families. American Journal of Medical Genetics. Part B-Neuropsychiatric Genetics 156B(5): 561-568, 2011. (53 refs.)

Multiple genetic and environmental factors influence the risk for both major depression and alcohol/substance use disorders. In addition, there is evidence that these illnesses share genetic factors. Although, the heritability of these illnesses is well established, relatively few studies have focused on ethnic minority populations. Here, we document the prevalence, heritability, and genetic correlations between major depression and alcohol and drug disorders in a large, community-ascertained sample of Mexican-American families. A total of 1,122 Mexican-American individuals from 71 extended pedigrees participated in the study. All subjects received in-person psychiatric interviews. Heritability, genetic, and environmental correlations were estimated using SOLAR. Thirty-five percent of the sample met criteria for DSM-IV lifetime major depression, 34% met lifetime criteria for alcohol use disorders, and 8% met criteria for lifetime drug use disorders. The heritability for major depression was estimated to be h(2) = 0.393 (P = 3.7 x 10(-6)). Heritability estimates were higher for recurrent depression (h(2) = 0.463, P = 4.0 x 10(-6)) and early onset depression (h(2) = 0.485, P = 8.5 x 10(-5)). While the genetic correlation between major depression and alcohol use disorders was significant (rho(g) = 0.58, P = 7 x 10(-3)), the environmental correlation between these traits was not significant. Although, there is evidence for increased rates of depression and substance use in US-born individuals of Mexican ancestry, our findings indicate that genetic control over major depression and alcohol/substance use disorders in the Mexican-American population is similar to that reported in other populations.

Park A; Sher KJ; Todorov AA; Heath AC. Interaction between the DRD4 VNTR polymorphism and proximal and distal environments in alcohol dependence during emerging and young adulthood. Journal of Abnormal Psychology 120(3): 585-595, 2011. (80 refs.)

The manifestation of alcohol dependence at different developmental stages may be associated with different genetic and environmental factors. Taking a developmental approach, we characterized interaction between the dopamine receptor 4 variable number tandem repeat (DRD4 VNTR) polymorphism and developmentally specific environmental factors (childhood adversity, college/Greek organization involvement, and delayed adult role transition) on alcohol dependence during emerging and young adulthood. Prospective data were obtained from a cohort of 234 White individuals (56% women, 44% men) who were followed up at ages 18 through 34. A longitudinal hierarchical factor model was estimated to model a traitlike persistent alcohol dependence factor throughout emerging and young adulthood and 2 residual statelike alcohol dependence factors limited to emerging adulthood and young adulthood, respectively. We accounted for those alcohol dependence factors by modeling 3 two-way interaction effects between the DRD4 VNTR polymorphism and the 3 developmentally specific environment factors. Carriers of the DRD4 long allele showed greater susceptibility to environmental effects; they showed more persistent symptoms of alcohol dependence as childhood adversity increased and more alcohol dependence symptoms limited to emerging adulthood as college/Greek organization involvement increased. Alcohol dependence among noncarriers of the long allele, however, did not differ as a function of those environments. Although replication is necessary, these findings highlight the importance of repeated phenotypic assessments across development and modeling both distal and proximal environments and their interaction with genetic susceptibility at specific developmental stages.

Pavanello S; Hoxha M; Dioni L; Bertazzi PA; Snenghi R; Nalesso A et al. Shortened telomeres in individuals with abuse in alcohol consumption. International Journal of Cancer 129(4): 983-992, 2011. (48 refs.)

Alcohol abuse leads to earlier onset of aging-related diseases, including cancer at multiple sites. Shorter telomere length (TL) in peripheral blood leucocytes (PBLs), a marker of biological aging, has been associated with alcohol-related cancer risks. Whether alcohol abusers exhibit accelerated biological aging, as reflected in PBL-TL, has never been examined. To investigated the effect of alcohol abuse on PBL-TL and its interaction with alcohol metabolic genotypes, we examined 200 drunk-driving traffic offenders diagnosed as alcohol abusers as per the Diagnostic and Statistical Manual of Mental Disorders [DSM-IV-TR] and enrolled in a probation program, and 257 social drinkers (controls). We assessed alcohol intake using self-reported drink-units/day and conventional alcohol abuse biomarkers (serum gamma-glutamyltrasferase [GGT] and mean corpuscular volume of erythrocytes [MCV]). We used multivariable models to compute TL geometric means (GM) adjusted for age, smoking, BMI, diet, job at elevated risk of accident, genotoxic exposures. TL was nearly halved in alcohol abusers compared with controls (GMs 0.42 vs. 0.87 relative T/S ratio; p < 0.0001) and decreased in relation with increasing drink-units/day (p-trend = 0.003). Individuals drinking >4 drink-units/day had substantially shorter TL than those drinking <= 4 drink-units/day (GMs 0.48 vs. 0.61 T/S, p = 0.002). Carriers of the common ADH1B*1/*1 (rs1229984) genotype were more likely to be abusers (p = 0.008), reported higher drink-units/day (p = 0.0003), and exhibited shorter TL (p < 0.0001). The rs698 ADH1C and rs671 ALDH2 polymorphisms were not associated with TL. The decrease in PBL-TL modulated by the alcohol metabolic genotype ADH1B*1/*1 may represent a novel mechanism potentially related to alcohol carcinogenesis in alcohol abusers.

Pei J; Denys K; Hughes J; Rasmussen C. Mental health issues in fetal alcohol spectrum disorder. (review). Journal of Mental Health 20(5): 473-483, 2011. (48 refs.)

Background. High numbers of individuals with Fetal Alcohol Spectrum Disorders (FASD) have been described as having mental health problems. Aims. This article summarizes research about mental health problems in FASD and considers related developmental and environmental issues. Method. A computer-based literature search was conducted in the databases Medline, PsycINFO, Google Scholar, Academic Search Complete, and Education Resources Information Centre for articles addressing the prevalence and types of mental health issues in individuals affected by FASD. Results. High rates of mental disorders within the FASD and prenatal alcohol exposure (PAE) population were found to be consistently reported for both internalizing and externalizing disorders. Moreover, problems that emerge in childhood may reflect a convergence of genetic, environmental, and neurophysiological factors that persist into adulthood. Conclusions. Researchers are beginning to document the impacts of PAE on later mental health development. Further longitudinal study is needed to determine whether there is an increasing severity of mental health deficits and consequences with age, and whether any such changes reflect increasingly deteriorating environmental factors or brain-based factors. Additionally, research is needed to design interventions to better address the unique mental health needs of this population.

Quinn PD; Fromme K. Subjective response to alcohol challenge: A quantitative review. (review). Alcoholism: Clinical and Experimental Research 35(10): 1759-1770, 2011. (80 refs.)

Background: Individual differences in subjective response to alcohol, as measured by laboratory-based alcohol challenge, have been identified as a candidate phenotypic risk factor for the development of alcohol-use disorders (AUDs). Two models have been developed to explain the role of subjective response to alcohol, but predictions from the 2 models are contradictory, and theoretical consensus is lacking. Methods: This investigation used a meta-analytic approach to review the accumulated evidence from alcohol-challenge studies of subjective response as a risk factor. Data from 32 independent samples (total N = 1,314) were aggregated to produce quantitative estimates of the effects of risk-group status (i.e., positive family history of AUDs or heavier alcohol consumption) on subjective response. Results: As predicted by the Low Level of Response Model (LLRM), family history-positive groups experienced reduced overall subjective response relative to family history-negative groups. This effect was most evident among men, with family history-positive men responding more than half a standard deviation less than family history-negative men. In contrast, consistent with the Differentiator Model (DM), heavier drinkers of both genders responded 0.4 standard deviations less on measures of sedation than did the lighter drinkers but nearly half a standard deviation more on measures of stimulation, with the stimulation difference appearing most prominent on the ascending limb of the blood alcohol concentration curve. Conclusions: The accumulated results from 3 decades of family history comparisons provide considerable support for the LLRM. In contrast, results from typical consumption comparisons were largely consistent with predictions of the DM. The LLRM and DM may describe 2 distinct sets of phenotypic risk, with importantly different etiologies and predictions for the development of AUDs.

Ramchandani VA; Umhau J; Pavon FJ; Ruiz-Velasco V; Margas W; Sun H et al. A genetic determinant of the striatal dopamine response to alcohol in men. Molecular Psychiatry 16(8): 809-817, 2011. (59 refs.)

Excessive alcohol use, a major cause of morbidity and mortality, is less well understood than other addictive disorders. Dopamine release in ventral striatum is a common element of drug reward, but alcohol has an unusually complex pharmacology, and humans vary greatly in their alcohol responses. This variation is related to genetic susceptibility for alcoholism, which contributes more than half of alcoholism risk. Here, we report that a functional OPRM1 A118G polymorphism is a major determinant of striatal dopamine responses to alcohol. Social drinkers recruited based on OPRM1 genotype were challenged in separate sessions with alcohol and placebo under pharmacokinetically controlled conditions, and examined for striatal dopamine release using positron emission tomography and [(11)C]-raclopride displacement. A striatal dopamine response to alcohol was restricted to carriers of the minor 118G allele. To directly establish the causal role of OPRM1 A118G variation, we generated two humanized mouse lines, carrying the respective human sequence variant. Brain microdialysis showed a fourfold greater peak dopamine response to an alcohol challenge in h/mOPRM1-118GG than in h/mOPRM1-118AA mice. OPRM1 A118G variation is a genetic determinant of dopamine responses to alcohol, a mechanism by which it likely modulates alcohol reward.

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.

Ray LA. Stress-induced and cue-induced craving for alcohol in heavy drinkers: Preliminary evidence of genetic moderation by the OPRM1 and CRH-BP genes. Alcoholism: Clinical and Experimental Research 35(1): 166-174, 2011. (58 refs.)

Background: Neurobiological theories of addiction have highlighted disruption in stress pathways as a central feature of addictive disorders, and pharmacological treatments targeting stress mechanisms hold great promise. This study examines genetic determinants of stress-induced and cue-induced craving in heavy drinkers by testing single-nucleotide polymorphisms (SNPs) of the corticotrophin-releasing hormone binding protein (CRH-BP) gene and the mu-opioid receptor (OPRM1) gene. Methods: This study combines guided imagery stress exposure and in vivo alcohol cue exposure in a sample of 64 (23 women) non-treatment-seeking heavy drinkers. Results: Analyses, uncorrected for multiple comparisons, revealed that a tag SNP of the CRH-BP gene (rs10055255) moderated stress-induced craving in this sample. The same SNP predicted greater affective responses to the stress manipulation, including greater levels of subjective tension and negative mood. The Asp40 allele of the OPRM1 was associated with greater cue-induced alcohol craving following the neutral imagery condition. Conclusions: These initial results extend recent preclinical and clinical findings implicating the CRH-BP in stress-related alcoholism and confirm the role of the Asp40 allele of the OPRM1 gene in reward-driven alcohol phenotypes. Human laboratory models of stress and cue-induced craving may be useful in pharmacotherapy development targeting dysregulation of stress systems. Larger studies are needed to validate these preliminary findings, which should also be extended to clinical samples.

Ribbe K; Ackermann V; Schwitulla J; Begemann M; Papiol S; Grube S et al. Prediction of the risk of comorbid alcoholism in schizophrenia by interaction of common genetic variants in the corticotropin-releasing factor system. Archives of General Psychiatry 68(12): 1247-1256, 2011. (71 refs.)

Context: Stress plays a major role in the development of comorbid alcohol use disorder (AUD). In turn, AUD worsens the outcome of psychiatric patients with respect to global disease severity, social situation, and socioeconomic burden. Prediction of persons at risk for AUD is crucial for future preventive and therapeutic strategies. Objective: To investigate whether genetic variants of the corticotropin-releasing factor system or their interaction influence the risk of developing AUD in chronic disease populations. Design: Genotype analysis comprising selected single-nucleotide polymorphisms within the CRHR1 and CRHBP genes in patients with schizophrenia and in a nonschizophrenic psychiatric disease control sample should allow the extraction of predictors of comorbid AUD. Gene expression (messenger RNA) analysis in peripheral blood mononuclear cells was performed to gain the first mechanistic insight. Setting: An ideal setup for this study was the Gottingen Research Association for Schizophrenia Data Collection of schizophrenic patients, specifically intended to enable association of genetic information with quantifiable phenotypes in a phenotype-based genetic association study. Patients: A total of 1037 schizophrenic patients (Gottingen Research Association for Schizophrenia sample), 80 nonschizophrenic psychiatric disease controls as a small replicate sample, and a case-control study including 1141 healthy subjects. Main Outcome Measures: Association of CRHR1 and CRHBP genotypes with the following: (1) AUD; (2) a newly developed alcoholism severity score comprising 5 AUD-relevant variables; and (3) quantitative CRHR1 and CRHBP messenger RNA expression. Results: An interaction of CRHR1 rs110402 and CRHBP rs3811939 predicts high risk of comorbid AUD in schizophrenic patients (odds ratio = 2.27; 95% confidence interval, 1.56-3.30; P<.001) as well as psychiatric disease controls (odds ratio= 4.02; 95% confidence interval, 0.95-17.05; P=.06) and leads to the highest CRHR1/CRHBP messenger RNA ratio (P=.02; dysbalanced stress axis). Conclusions: The high predictive value of a genetic interaction within the stress axis for the risk of comorbid AUD may be used for novel preventive and individualized therapeutic approaches.

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.

Roh S; Matsushita S; Hara S; Maesato H; Matsui T; Suzuki G et al. Role of GABRA2 in moderating subjective responses to alcohol. Alcoholism: Clinical and Experimental Research 35(3): 400-407, 2011. (54 refs.)

Background: Human twin studies have shown that certain responses to alcohol, including subjective perceptions, are genetically influenced. Previous studies have provided evidence that a low level of response to alcohol predicts future alcohol use disorders in humans. Recent genetic studies suggest an association between alcohol dependence and genetic variation in the gamma-aminobutyric acid A (GABA(A)) receptor alpha 2 subunit gene (GABRA2). Based on a haplotypic association of alcohol dependence with GABRA2, we investigated whether GABRA2 alleles are associated with the subjective responses to clamped alcohol concentration. Methods: One hundred and ten healthy social drinkers (53 men) underwent the alcohol clamp. Fifteen minutes after the start of an intravenous infusion of alcohol, the breath alcohol concentration was clamped at a target of 50 +/- 5 mg/dl for 165 minutes. Subjective physiologic responses to alcohol and stimulant and sedative effects of alcohol were measured repeatedly during the alcohol clamp. Because aldehyde dehydrogenase 2 (ALDH2) has been shown to have a great impact on the subjective responses to alcohol, we divided subjects by ALDH2 genotype for further analyses. To examine the role of genetic variation in GABRA2, 7 single nucleotide polymorphisms (SNPs) that were informative in association studies were included as factors in the analysis. Results: Among these 7 SNPs, 3 SNPs (rs279869, rs279858, and rs279837) located in the middle of the GABRA2 gene showed significant associations with subjective effects of alcohol. Subjects with 1 or 2 copies of the more common allele showed greater subjective responses to alcohol than did individuals homozygous for the alcohol dependence associated allele regardless of ALDH2 genotype. Conclusions: These findings confirm and extend the observation that the GABRA2 alleles affect the subjective responses to alcohol, and suggest that the genetic variations in GABRA2 might play a role in the risk of alcohol use disorders by moderating the subjective effects of alcohol.

Sartor CE; McCutcheon VV; Pommer NE; Nelson EC; Grant JD; Duncan AE et al. Common genetic and environmental contributions to post-traumatic stress disorder and alcohol dependence in young women. Psychological Medicine 41(7): 1497-1505, 2011. (41 refs.)

Background. The few genetically informative studies to examine post-traumatic stress disorder (PTSD) and alcohol dependence (AD), all of which are based on a male veteran sample, suggest that the co-morbidity between PTSD and AD may be attributable in part to overlapping genetic influences, but this issue has yet to be addressed in females. Method. Data were derived from an all-female twin sample (n=3768) ranging in age from 18 to 29 years. A trivariate genetic model that included trauma exposure as a separate phenotype was fitted to estimate genetic and environmental contributions to PTSD and the degree to which they overlap with those that contribute to AD, after accounting for potential confounding effects of heritable influences on trauma exposure. Results. Additive genetic influences (A) accounted for 72% of the variance in PTSD; individual-specific environmental (E) factors accounted for the remainder. An AE model also provided the best fit for AD, for which heritability was estimated to be 71%. The genetic correlation between PTSD and AD was 0.54. Conclusions. The heritability estimate for PTSD in our sample is higher than estimates reported in earlier studies based almost exclusively on an all-male sample in which combat exposure was the precipitating traumatic event. However, our findings are consistent with the absence of evidence for shared environmental influences on PTSD and, most importantly, the substantial overlap in genetic influences on PTSD and AD reported in these investigations. Additional research addressing potential distinctions by gender in the relative contributions of genetic and environmental influences on PTSD is merited.

Schuckit MA; Smith TL; Trim RS; Allen RC; Fukukura T; Knight EE et al. A prospective evaluation of how a low level of response to alcohol predicts later heavy drinking and alcohol problems. American Journal of Drug and Alcohol Abuse 37(6): 479-486, 2011. (45 refs.)

Background and objectives: Evaluations of how a genetically influenced characteristic, such as the low level of response (a low LR) to alcohol, relates to later heavy drinking and alcohol problems usually include environmental contributors. The best way to understand how LR works in the context of these additional characteristics is to study the process prospectively, but such analyses tend to be complex and the papers are sometimes cluttered with jargon. This report attempts to offer a more straightforward description of the results from such a prospective model of how a lower LR at age 20 relates to alcohol outcomes at age 40. Methods: A structural equation model of LR at age similar to 20, outcomes of heavy drinking and problems at age similar to 40, and additional characteristics at age similar to 35 were tested in 378 men from the San Diego Prospective Study. Results: The results support both direct effects of age-20 LR on age-40 heavy drinking and alcohol problems, as well as indirect effects of LR through characteristics of these men at age 35. The latter include using alcohol to cope with stress and heavier drinking among peers. Conclusions: A low LR to alcohol is an example of how both genes and environment can contribute to the risk for adverse alcohol outcomes. The identification of mechanisms through which LR impacts on later heavy drinking and problems can be approached in cross-sectional studies, but those may not be as sensitive as longitudinal models for identifying additional potential mediators of the LR-to-outcome relationship.

Schuckit MA; Smith TL; Heron J; Hickman M; Macleod J; Lewis G et al. Testing a level of response to alcohol-based model of heavy drinking and alcohol problems in 1,905 17-year-olds. Alcoholism: Clinical and Experimental Research 35(10): 1897-1904, 2011. (56 refs.)

Background: The low level of response (LR) to alcohol is one of several genetically influenced characteristics that increase the risk for heavy drinking and alcohol problems. Efforts to understand how LR operates through additional life influences have been carried out primarily in modest-sized U.S.-based samples with limited statistical power, raising questions about generalizability and about the importance of components with smaller effects. This study evaluates a full LR-based model of risk in a large sample of adolescents from the United Kingdom. Methods: Cross-sectional structural equation models were used for the approximate first half of the age 17 subjects assessed by the Avon Longitudinal Study of Parents and Children, generating data on 1,905 adolescents (mean age 17.8 years, 44.2% boys). LR was measured with the Self-Rating of the Effects of Alcohol Questionnaire, outcomes were based on drinking quantities and problems, and standardized questionnaires were used to evaluate peer substance use, alcohol expectancies, and using alcohol to cope with stress. Results: In this young and large U.K. sample, a low LR related to more adverse alcohol outcomes both directly and through partial mediation by all 3 additional key variables (peer substance use, expectancies, and coping). The models were similar in boys and girls. Conclusions: These results confirm key elements of the hypothesized LR-based model in a large U.K. sample, supporting some generalizability beyond U.S. groups. They also indicate that with enough statistical power, multiple elements contribute to how LR relates to alcohol outcomes and reinforce the applicability of the model to both genders.

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

Shin CM; Kim N; Cho SI; Kim JS; Jung HC; Song IS. Association between alcohol intake and risk for gastric cancer with regard to ALDH2 genotype in the Korean population. International Journal of Epidemiology 40(4): 1047-1055, 2011. (32 refs.)

Methods: From 2003 to 2008, 445 patients with gastric cancer and 370 control subjects 50 years of age were included in the analysis. Logistic regression models including age, gender, education, smoking and drinking status, Helicobacter pylori infection and ALDH2 genotype were evaluated to estimate the adjusted odds ratios (ORs) for the development of gastric cancer. Results For all subjects, the risk for gastric cancer was increased in ex-drinkers [OR 1.68, 95% confidence interval (CI) 1.07-2.64], but not in current drinkers. Subjects with inactive ALDH2 *2 allele(s) showed a lower level of alcohol consumption than ALDH2 *1/*1 homozygotes (P < 0.001). Among the ALDH2 *1/*2 carriers (n = 243), current/ex-drinkers had a significantly increased risk for gastric cancer compared with never/rare drinkers (OR 2.80, 95% CI 1.51-5.19). Among heavy drinkers (n = 115), ALDH2 *1/*2 heterozygotes had a 4-fold increased risk for gastric cancer compared with *1/*1 homozygotes (OR 4.26, 95% CI 1.10-16.47); however, no risk increase was seen among never/rare drinkers. Conclusions: A dose-response association between alcohol intake and the risk for gastric cancer was not observed. However, ALDH2 polymorphisms were found to modify the susceptibility to the development of gastric cancer associated with alcohol intake, especially in case of ALDH2 *1/*2 genotype. The findings suggest an alcohol-ALDH2 genotype interaction in gastric carcinogenesis.

Silveri MM; Rogowska J; McCaffrey A; Yurgelun-Todd DA. Adolescents at risk for alcohol abuse demonstrate altered frontal lobe activation during Stroop Performance. (review). Alcoholism: Clinical and Experimental Research 35(2): 218-228, 2011. (105 refs.)

Background: Children and adolescents, family history positive (FH+) for alcoholism, exhibit differences in brain structure and functional activation when compared to family history negative (FH-) counterparts. Given that frontal brain regions, and associated reciprocal connections with limbic structures, undergo the most dramatic maturational changes during adolescence, the objective of this study was to compare functional brain activation during a frontally mediated test of response inhibition in 32 adolescents separated into low-risk (FH-) and high-risk (FH+) groups. Methods: Functional magnetic resonance (fMRI) blood oxygen level-dependent data were acquired at 1.5 Tesla during performance of Stroop Color Naming, Word Reading, and Interference. Preprocessing and statistical analyses, covaried for age, were conducted in SPM99 using a search territory that included superior, middle, and inferior frontal gyri (trigone region), anterior cingulate gyrus (CG), and left and right amygdala. Results: Significantly greater activation in the fronto-limbic search territory was observed in FH+ relative to FH- subjects during Stroop Interference. In addition, a significant regression between brain activation and family history density was observed, with a greater density being associated with increased activation in regions including middle frontal gyrus (BA9) and CG (BA24). Conclusions: These data demonstrate a significant influence of FH status on brain activation during the performance of a response inhibition task, perhaps reflecting a neurobiological vulnerability associated with FH status that may include reduced neuronal efficiency and/or recruitment of additional neuronal resources. These findings are important given that the adolescent developmental period is already associated with reduced inhibitory capacity, even prior to the onset of alcohol use.

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.

Takeuchi F; Isono M; Nabika T; Katsuya T; Sugiyama T; Yamaguchi S et al. Confirmation of ALDH2 as a major locus of drinking behavior and of its variants regulating multiple metabolic phenotypes in a Japanese population. Circulation Journal 75(4): 911-918, 2011. (39 refs.)

Background: Normative alcohol use (or drinking behavior) influences the risk of cardiovascular disease in a multi-faceted manner. To identify susceptibility gene variants for drinking behavior, a 2-staged genome-wide association study was performed in a Japanese population. Methods and Results: In the stage-1 scan, 733 cases and 729 controls were genotyped with 456,827 SNP markers. The associated loci without redundancy of linkage disequilibrium were further examined in the stage-2 general population panel comprising 2,794 drinkers (>= once per week), 1,521 chance drinkers (Copyright 2011, Japanese Circulation Society

Tao MH; Marian C; Shields PG; Nie J; McCann SE; L. Alcohol consumption in relation to aberrant DNA methylation in breast tumors. Alcohol 45(7): 689-699, 2011. (47 refs.)

The mechanism for the observed association of alcohol consumption breast cancer risk is not known; understanding that mechanism could improve understanding of breast carcinogenesis and optimize prevention strategies. Alcohol may impact breast malignancies or tumor progression by altering DNA methylation. We examined promoter methylation of three genes, the E-cadherin, pl6, and retinoic acid-binding receptor-beta 2 (RAR-beta(2)) genes in archived breast tumor tissues from participants in a population-based case-control study. Real time methylation-specific PCR was performed on 803 paraffin-embedded samples, and lifetime alcohol consumption was queried. Unordered polytomous and unconditional logistic regression were used to derive adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RAR-beta(2) methylation was not associated with drinking. Among premenopausal women, alcohol consumption was also not associated with promoter methylation for E-cadherin and pl6 genes. In case-case comparisons of postmenopausal breast cancer, compared with lifetime never drinkers, promoter methylation likelihood was increased for higher alcohol intake for E-cadherin (OR = 2.39; 95% CI, 1.15-4.96), in particular for those with estrogen receptor-negative tumors (OR = 4.13; 95% CI, 1.16-14.72), and decreased for pl6 (OR = 0.52; 95% CI, 0.29-0.92). There were indications that the association with pl6 was stronger for drinking at younger ages. Methylation was also associated with drinking intensity independent of total consumption for both genes. We found alcohol consumption was associated with DNA methylation in postmenopausal breast tumors, suggesting that the association of alcohol and breast cancer may be related, at least in part, to altered methylation, and may differ by drinking pattern.

Thombs DL; O'Mara RJ; Hou W; Wagenaar AC; Dong HJ; Merves ML et al. 5-HTTLPR genotype and associations with intoxication and intention to drive: Results from a field study of bar patrons. Addiction Biology 16(1): 133-141, 2011. (27 refs.)

The serotonin transporter promoter polymorphism (5-HTTLPR) has been linked to a number of human behavioral traits and disorders. The variants of 5-HTTLPR are commonly reported in three forms, L/L, S/L and S/S, with the latter most often associated with emotional distress and/or behavioral dysfunction. Missing from the research literature are investigations that assess event-level associations between 5-HTTLPR genotype and specific incidents of risk behavior in natural drinking settings. This study reports associations between 5-HTTLPR, alcohol intoxication and intention to drive among young adult patrons exiting on-premise drinking establishments (i.e. bars) at night. Self-report measures, breath alcohol concentration (BrAC) readings and saliva samples for DNA analysis were collected from 477 bar patrons. Analyses were performed on 225 patrons likely to be near their peak intoxication level for the night. Results from a linear regression revealed that the 5-HTTLPR genotype was associated with exiting patron BrAC, after adjusting for random and fixed effects of other variables. An interaction effect involving 5-HTTLPR and bar-sponsored drink specials also had an independent association with BrAC, suggesting that selection of price-discounted alcoholic beverages increased intoxication in patrons with an L allele. In addition, results from logistic regression indicated that patrons with the S/S genotype were three times more likely to intend to drive a motor vehicle (after drinking on the night of study participation) compared with those with the L/L genotype. The 5-HTTLPR genotype may play an important role in the etiology of problems associated with on-premise drinking establishments.

Tolentino NJ; Wierenga CE; Hall S; Tapert SF; Paulus MP; Liu TT et al. Alcohol effects on cerebral blood flow in subjects with low and high responses to alcohol. Alcoholism: Clinical and Experimental Research 35(6): 1034- 1040, 2011. (55 refs.)

Background: Although there are multiple indications that alcohol can alter many physiological brain functions, including cerebral blood flow (CBF), studies of the latter have generally used small- or modest-sized samples. Few investigations have yet evaluated how CBF changes after alcohol relate to subsets of subjects with elevated alcoholism risks, such as those with lower levels of response (LR) to alcohol. This study used arterial spin labeling (ASL) after alcohol administration to evaluate a large sample of healthy young men and women with low and high alcohol responses, and, thus, varying risks for alcohol use disorders (AUD). Methods: Healthy young adult social drinkers with low and high LR (N = 88, 50% women) matched on demography and drinking histories were imaged with whole-brain resting ASL similar to 1 hour after ingesting similar to 3 drinks of ethanol and after a placebo beverage (i.e., 178 ASL sessions). The relationships of CBF changes from placebo to alcohol for subjects with low and high LR were evaluated. Results: CBF increased after alcohol when compared to placebo in 5 frontal brain regions. Despite identical blood alcohol concentrations, these increases with alcohol were less prominent in individuals who required more drinks to experience alcohol-related effects (i.e., had a lower LR to alcohol). The LR group differences remained significant after covarying for recent drinking quantities. Conclusions: The results confirm that alcohol intake is associated with acute increases in CBF, particularly in frontal regions. Less intense CBF changes were seen in subjects with a genetically influenced characteristic, a low LR to alcohol, that relates to the future risk of heavy drinking and alcohol problems.

Torvik FA; Rognmo K; Ask H; Roysamb E; Tambs K. Parental alcohol use and adolescent school adjustment in the general population: Results from the HUNT study. BMC Public Health 11: AR 706, 2011. (58 refs.)

Background: This study investigates the relationship between parental drinking and school adjustment in a total population sample of adolescents, with independent reports from mothers, fathers, and adolescents. As a group, children of alcohol abusers have previously been found to exhibit lowered academic achievement. However, few studies address which parts of school adjustment that may be impaired. Both a genetic approach and social strains predict elevated problem scores in these children. Previous research has had limitations such as only recruiting cases from clinics, relying on single responders for all measures, or incomplete control for comorbid psychopathology. The specific effects of maternal and paternal alcohol use are also understudied. Methods: In a Norwegian county, 88% of the population aged 13-19 years participated in a health survey (N = 8984). Among other variables, adolescents reported on four dimensions of school adjustment, while mothers and fathers reported their own drinking behaviour. Mental distress and other control variables were adjusted for. Multivariate analysis including generalized estimation equations was applied to investigate associations. Results: Compared to children of light drinkers, children of alcohol abusers had moderately elevated attention and conduct problem scores. Maternal alcohol abuse was particularly predictive of such problems. Children of abstainers did significantly better than children of light drinkers. Controlling for adolescent mental distress reduced the association between maternal abuse and attention problems. The associations between parental reported drinking and school adjustment were further reduced when controlling for the children's report of seeing their parents drunk, which itself predicted school adjustment. Controlling for parental mental distress did not reduce the associations. Conclusions: Parental alcohol abuse is an independent risk factor for attention and conduct problems at school. Some of the risk associated with mothers' drinking is likely to be mediated by adolescent mental distress. Despite lowered adjustment on the externalizing dimensions, children of alcohol abusers report that they enjoy being at school as much as other children.

Wang KS; Liu XF; Aragam N; Jian XQ; Mullersman JE; Liu YL et al. Family-based association analysis of alcohol dependence in the COGA sample and replication in the Australian twin-family study. Journal of Neural Transmission 118(9): 1293-1299, 2011. (53 refs.)

Family, twin, and adoption studies have indicated that genetic and environmental factors contribute to the development of alcohol dependence (AD). We conducted a low-density genome-wide association analysis to identify genetic variants influencing AD. We used 11,120 SNPs from the Affymetrix 10K Genechips genotyped in 116 Caucasian pedigrees (272 nuclear families) from Genetic Analysis Workshop 14, a subset from the Collaborative Study on the Genetics of Alcoholism (COGA). Family-based association analyses for AD were performed by the PBAT program for autosomal SNPs and by the FBAT program for X-chromosome SNPs. We identified 37 SNPs associated with AD (P < 10(-3)), thirteen of which were located in known genes. The most significant association with AD was observed with SNP rs1986644 (P = 8.51 x 10(-6)) at 13q22 near EDNRB gene. The next best signal was at 1q41 in USH2A (rs532342, P = 1.07 x 10(-5)) and the third region was at 3q25.31 in TIPARP (rs1367311, P = 2.31 x 10(-5)). Furthermore, we found support for association of MAOA gene (P = 4.14 x 10(-4) for rs979606). Six of the 37 AD associated SNPs were confirmed to be associated with AD in Australian twin-family study sample (P < 0.05). Interestingly, four SNPs in DSCAML1 at 11q23 reached the genome-wide significance (the top SNP is rs10892169 with P = 5.31 x 10(-9)), while rs637547 in NKAIN2 at 6q21 showed strong association with AD (P = 5.11 x 10(-7)) in the replication sample. These findings offer the potential for new insights into the pathogenesis of AD and will serve as a resource for replication in other populations to elucidate the potential role of these genetic variants in AD.

Webb A; Lind PA; Kalmijn J; Feiler HS; Smith TL; Schuckit MA et al. The investigation into CYP2E1 in relation to the level of response to alcohol through a combination of linkage and association analysis. Alcoholism: Clinical and Experimental Research 35(1): 10-18, 2011. (50 refs.)

Background: A low level of response to alcohol during an individual's early experience with alcohol is associated with an increase risk of alcoholism. A family-based genome-wide linkage analysis using sibling pairs that underwent an alcohol challenge where the level of response to alcohol was measured with the Subjective High Assessment Scale (SHAS) implicated the 10q terminal (10qter) region. CYP2E1, a gene known for its involvement with ethanol metabolism, maps to this region. Methods: Variance component multipoint linkage analysis was performed on a combined map of single-nucleotide polymorphism (SNP) and microsatellite data. To account for the heterogeneity evident in the dataset, a calculation assuming locus heterogeneity was made using the Heterogeneity Log of Odds (HLOD) score. Association between SNP marker allele counts and copy number and SHAS scores were evaluated using a logistic regression model. Results: Linkage analysis detected significant linkage to CYP2E1, which was diminished because of apparent locus heterogeneity traced to a single family with extreme phenotypes. In retrospect, circumstances recorded during testing for this family suggest that their phenotype data are likely to be unreliable. Significant allelic associations were detected for several CYP2E1 polymorphisms and the SHAS score. DNA sequencing from families that contributed the greatest evidence for linkage did not detect any changes directly affecting the primary amino acid sequence. With the removal of a single family, combined evidence from microsatellites and SNPs offers significant linkage between the level of response to alcohol and the region on the end of chromosome 10. Conclusion: Combined linkage and association indicate that sequence changes in or near CYP2E1 affect the level of response to alcohol providing a predictor of risk of alcoholism. The absence of coding sequence changes indicates that regulatory sequences are responsible. Implicating CYP2E1 in the level of response to alcohol allows inferences to be made about how the brain perceives alcohol.

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.

Wrzosek M; Lukaszkiewicz J; Wrzosek M; Serafin P; Jakubczyk A; Klimkiewicz A et al. Association of polymorphisms in HTR2A, HTR1A and TPH2 genes with suicide attempts in alcohol dependence: A preliminary report. Psychiatry Research 190(1): 149-151, 2011. (26 refs.)

We investigated a relationship between selected polymorphisms: rs6313 in HTR2A, rs6295 in HTR1A and rs1386494 in 7PH2, and suicidal behaviour in 150 alcohol-dependent patients. There was a significant association between more frequent C102C genotype in HTR2A and suicide attempts in alcoholic females. No differences in genotype distribution in HTR1A and TPH2 SNPs were found between patients with and without suicide attempts.

Yang ARST; Liu Juan; Yi Heon S; Warnock KT; Wang M; June HL Jr et al. Binge drinking: In search of its molecular target via the GABA(A) receptor. Frontiers In Neuroscience 5: e-123, 2011

Binge drinking, frequently referred to clinically as problem or hazardous drinking, is a pattern of excessive alcohol intake characterized by blood alcohol levels >0.08g% within a 2-h period. Here, we show that overexpression of alpha1 subunits of the GABA(A) receptor contributes to binge drinking, and further document that this involvement is related to the neuroanatomical localization of alpha1 receptor subunits. Using a herpes simplex virus amplicon vector to deliver small interference RNA (siRNA), we showed that siRNA specific for the alpha1 subunit (pHSVsiLA1) caused profound, long-term, and selective reduction of gene expression, receptor density, and binge drinking in high-alcohol drinking rats when delivered into the ventral pallidum (VP). Scrambled siRNA (pHSVsiNC) delivered similarly into the VP failed to alter gene expression, receptor density, or binge drinking. Silencing of the alpha1 gene in the VP, however, failed to alter binge sucrose or water intake. These results, along with our prior research, provide compelling evidence that the alpha1-containing GABA(A) receptor subunits are critical in the regulation of binge-like patterns of excessive drinking. Collectively, these data may be useful in the development of gene-based and novel pharmacological approaches for the treatment of excessive drinking.

Ystrom E; Reichborn-Kjennerud T; Aggen SH; Kendler KS. Alcohol dependence in men: Reliability and heritability. Alcoholism: Clinical and Experimental Research 35(9): 1716-1722, 2011. (34 refs.)

Background: The assessment of a Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) life-time history of alcohol dependence (LTH-AD) has been found to be moderately reliable and substantially heritable. However, in studies of the heritability of LTH-AD, measurement error could not be discriminated from the true unique environmental effects. The aims of this study were to: (i) estimate the reliability of LTH-AD in a population based sample, (ii) identify characteristics of LTH-AD predicting a reliable diagnosis, (iii) investigate the heritability of LTH-AD as a function of diagnostic confidence, and (iv) to estimate the genetic and environmental influences on LTH-AD correcting for measurement error. Methods: An unselected sample of 4,203 male twins was interviewed twice approximately 1-year apart assessing DSM-IV LTH-AD over the same period of life. Logistic regression was used to identify clinical features that predict a reliable diagnosis LTH-AD. Genetic and environmental influences on reliable LTH-AD were examined using structural equation models. Results: Reliability of the diagnosis of LTH-AD was moderate (kappa = 0.54) and was predicted by the number of AD symptoms, treatment seeking, duration of most severe episode, and a great deal of time spent to obtain, use, or recover from alcohol use (DSM-IV AD criterion #5). Using an index of caseness, heritability of LTH-AD increased as a function of diagnostic confidence. Accounting for errors of measurement in a multivariate twin model, the heritability of LTH-AD increased from 55 to 71%. Conclusions: Reliably diagnosed LTH-AD can be predicted by characteristics relevant to the disorder. LTH-AD appears to be a moderately reliable disorder of high heritability.

Zhang YM; Ren J. ALDH2 in alcoholic heart diseases: Molecular mechanism and clinical implications. (review). Pharmacology & Therapeutics 132(1): 86-95, 2011. (158 refs.)

Alcoholic cardiomyopathy is manifested as cardiac hypertrophy, disrupted contractile function and myofibrillary architecture. An ample amount of clinical and experimental evidence has depicted a pivotal role for alcohol metabolism especially the main alcohol metabolic product acetaldehyde, in the pathogenesis of this myopathic state. Findings from our group and others have revealed that the mitochondrial isoform of aldehyde dehydrogenase (ALDH2), which metabolizes acetaldehyde, governs the detoxification of acetaldehyde formed following alcohol consumption and the ultimate elimination of alcohol from the body. The ALDH2 enzymatic cascade may evolve as a unique detoxification mechanism for environmental alcohols and aldehydes to alleviate the undesired cardiac anomalies in ischemia-reperfusion and alcoholism. Polymorphic variants of the ALDH2 gene encode enzymes with altered pharmacokinetic properties and a significantly higher prevalence of cardiovascular diseases associated with alcoholism. The pathophysiological effects of ALDH2 polymorphism may be mediated by accumulation of acetaldehyde and other reactive aldehydes. Inheritance of the inactive ALDH2*2 gene product is associated with a decreased risk of alcoholism but an increased risk of alcoholic complications. This association is influenced by gene-environment interactions such as those associated with religion and national origin. The purpose of this review is to recapitulate the pathogenesis of alcoholic cardiomyopathy with a special focus on ALDH2 enzymatic metabolism. It will be important to dissect the links between ALDH2 polymorphism and prevalence of alcoholic cardiomyopathy, in order to determine the mechanisms underlying such associations. The therapeutic value of ALDH2 as both target and tool in the management of alcoholic tissue damage will be discussed.