Serving Substance Abuse Professionals Since 1993

Last Update: 29.03.08

C O R K O N L I N E

powerpoint presentations
CORK database search
resource materials
bibliographies
clinical tools
user services
newsletters
about cork
home

CORK Bibliography: Genetics and Alcohol Use

96 citations. January 2007 to present

Prepared: March 2008

Agrawal A; Dick DM; Bucholz KK; Madden PAF; Cooper ML; Sher KJ et al. Drinking expectancies and motives: A genetic study of young adult women. Addiction 103(2): 194-204, 2008. (50 refs.)

Background: Constructs such as drinking expectancies (beliefs regarding the effects of alcohol) and motives (drinking alcohol to achieve a valued end) have been shown to be associated with various stages of alcohol use behaviors. However, little is known of the extent to which genetic and environmental influences contribute to individual differences in expectancies and motives. Methods Using data from 3656 young adult same-sex female twins, we examined the association between measures of drinking expectancies and motives and drinking behaviors. Using twin models, we estimated the extent to which genetic, shared and non-shared environmental factors influenced individual differences in expectancies and motives and also tested whether the extent of the genetic and environmental contributions on expectancies varied across abstainers and users of alcohol. Results: Expectancies predicted initiation of alcohol use. Both motives and expectancies were associated with frequency and quantity of alcohol consumption and drinks-to-intoxication. There was no evidence for heritable influences on expectancies and enhancement motives, with familial similarity for these traits being due to shared environment. Heritable influences on social, coping and conformity motives ranged from 11% to 33%. When expectancies were stratified by alcohol use, significant heritable influences (31-39%) were found for cognitive-behavioral impairment and risk-taking/negative self-perception (RT/NSP) in abstainers only, while environmental influences contributed to familial variance for other measures of expectancies in alcohol users. Conclusions: Environmental influences (both familial and individual-specific) shape alcohol expectancies, while heritable influences may predispose to motives for drinking. Individual differences in expectancies are moderated by alcohol use, suggesting that sources of individual differences in expectancies may vary in drinkers versus abstainers.

Andersson C; Johnsson KO; Berglund M; Ojehagen A. Alcohol involvement in Swedish University freshmen related to gender, age, serious relationship and family history of alcohol problems. Alcohol and Alcoholism 42(5): 448-455, 2007. (45 refs.)

Aim: The primary aim of this study was to describe alcohol involvement in relation to gender and different age cohorts among freshmen at two Swedish universities. The secondary aim was to investigate whether the results were related to a likelihood of students being in serious relationships and/or had a first-degree relative with alcohol problems. Methods: Two complete cohorts of university freshmen at two homogeneous universities were asked to participate in an intervention study, and the results of the basic assessments are presented in this article. The following instruments were used: the Alcohol Use Disorders Identification Test (AUDIT), the Estimated Blood Alcohol Concentration (eBAC) and a shortened version of the Alcohol Expectancy Questionnaire (AEQ). Results: A total of 2032 (72%) freshmen agreed to participate. The mean AUDIT score was 8.8 (4.9) for men and 6.0 (+4.0) for women, and there were high correlations between the AUDIT and other instruments. There were significant differences between different age groups for both men and women. Both genders were more likely to have AUDIT scores higher than the usual cut-off levels for high-risk interventions among those with first-degree heredity of alcohol problems, while those students in serious relationships were less likely to have AUDIT scores above the usual cut-off levels for high-risk interventions. Conclusion: This study reveals a high level of alcohol involvement among Swedish university freshmen. This is affected by age, gender, heredity of alcohol problems and serious relationships.

Ball D. Genetics of addiction. Psychiatry 5(12): 446-448, 2006. (14 refs.)

The observation that addiction can run in families, and that this is in part determined by genetic factors, has been confirmed by family, twin and adoption studies. The actual genes that underpin this genetic contribution to vulnerability are being sought and identified using a combination of approaches including genetic linkage and association. Ultimately, the identification of the complex interaction between genes and environment that occurs during the process of addiction development will provide the framework through which potential treatment approaches can be developed and targeted.

Barnow S; Schuckit M; Smith T; Spitzer C; Freyberger HJ. Attention problems among children with a positive family history of alcohol abuse or dependence and controls: Prevalence and course for the period from preteen to early teen years. European Addiction Research 13(1): 1-5, 2007. (59 refs.)

This longitudinal study investigated the scope and course of attention problems over a period of time from preteen (ages 7-12 years) to early teen years (ages 13-17 years). We compared symptoms in subjects with and without a family history (FH) of alcohol abuse or dependence from among families without evidence of antisocial personality disorder. Evaluations of attention problems for the offspring were based on the Child Behavior Checklist and a validated semistructured interview carried out with the mother. The findings indicate no higher risk for attention problems and attention-deficit hyperactivity disorder (ADHD)-like symptoms in the children of families with an alcohol use disorder. Regarding the course of problems, the ADHD symptom count tended to decrease over time, especially for children without a FH of alcohol abuse or dependence. Further research will be needed to determine whether results can be replicated with families from different social strata and including subjects with the antisocial personality disorder.

Biederman J Petty CR Wilens TE Fraire MG Purcell CA Mick E et al. Familial risk analyses of attention deficit hyperactivity disorder and substance use disorders. American Journal of Psychiatry 165(1): 107-115, 2008. (37 refs.)

Objective: A robust and bidirectional comorbidity between attention deficit hyperactivity disorder (ADHD) and psychoactive substance use disorder (alcohol or drug abuse or dependence) has been consistently reported in the extant literature. Method: First-degree relatives from a large group of pediatrically and psychiatrically referred boys with (112 probands, 385 relatives) and without (105 probands, 358 relatives) ADHD were comprehensively assessed by blind raters with structured diagnostic interviews, Familial risk analysis examined the risks in first-degree relatives for ADHD, psychoactive substance use disorder, alcohol dependence, and drug dependence after stratifying probands by the presence and absence of these disorders. Results: ADHD in the proband was consistently associated with a significant risk for ADHD in relatives. Drug dependence in probands increased the risk for drug dependence in relatives irrespective of ADHD status, whereas alcohol dependence in relatives was predicted only by ADHD probands with comorbid alcohol dependence. in addition, ADHD in the proband predicted drug dependence in relatives, and drug dependence in comparison probands increased the risk for ADHD in relatives. Both alcohol dependence and drug dependence bred true in families without evidence for a common risk between these disorders. Conclusions: Patterns of familial risk analysis suggest that the association between ADHD and drug dependence is most consistent with the hypothesis of variable expressivity of a common risk between these disorders, whereas the association between ADHD and alcohol dependence is most consistent with the hypothesis of independent transmission of these disorders. Findings also suggest specificity for the transmission of alcohol and drug dependence.

Bleich S; Bonsch D; Rauh J; Bayerlein K; Fiszer R; Frieling H et al. Association of the long allele of the 5-httlpr polymorphism with compulsive craving in alcohol dependence. Alcohol and Alcoholism 42(6): 509-512, 2007. (31 refs.)

Aims: Various studies have reported a role of the serotonin transporter-linked polymorphic region (5-HTTLPR) in alcoholism. Method: The present study investigated an association of this polymorphism with obsessive-compulsive alcohol craving in 124 male patients admitted for alcohol detoxification treatment. Results: We found significantly higher compulsive craving in patients with the long allele of the 5-HTTLPR polymorphism [at admission: analysis of variance (ANOVA): F=3.48, P=0.034, general linear model: F=3.92, P=0.023; after 7days: ANOVA: F=3.12, P=0.049]. Conclusions: Our results suggest that the long variant of the 5-HTTLPR polymorphism is associated with higher compulsive alcohol craving at the beginning of alcohol withdrawal.

Button TMM; Rhee SH; Hewitt JK; Young SE; Corley RP; Stallings MC. The role of conduct disorder in explaining the comorbidity between alcohol and illicit drug dependence in adolescence. Drug and Alcohol Dependence 87(1): 46-53, 2007. (44 refs.)

Background: Conduct disorder (CD), alcohol dependence (AD), and illicit drug dependence (IDD) frequently co-occur. This paper describes the result of an investigation of the extent to which comorbid alcohol and illicit drug dependence in adolescents are explained by etiological factors in common with conduct disorder. Methods: Participants were 645 MZ twin pairs, 702 DZ twin pairs, 429 biological sibling pairs, and 96 adoptive sibling pairs, aged 12-18 years, from a community based sample. Conduct disorder was measured using the Diagnostic Interview Schedule for Children-IV Alcohol and illicit drug dependence were assessed using the Composite International Diagnostic Interview-Substance Abuse Module (CIDI-SAM). For each outcome, subjects were categorized into those with no symptoms, those with one or more symptoms but no diagnosis, and those with a diagnosis. Results: The heritability estimates for CD, AD, and IDD were 58, 66, and 36%, respectively. The genetic correlation between AD and IDD was partially explained by the genetic risk they both share with conduct disorder. Conclusions: We conclude that conduct disorder in adolescents explains, in part, the co-occurrence of alcohol and illicit drug dependence. Specifically, the genetic contribution to their covariation is explained partially by the genetic contribution in common with conduct disorder.

Chen YJ; Chen C; Wu DC; Lee CH; Wu CI; Lee JM et al. Interactive effects of lifetime alcohol consumption and alcohol and aldehyde dehydrogenase polymorphisins on esophageal cancer risks. International Journal of Cancer 119(12): 2827-2831, 2006. (32 refs.)

In our previous study, we found that polymorphisms of alcohol and aldehyde dehydrogenase (ADH1B and ALDH2) are important risks for esophageal squamous cell carcinoma in a Taiwanese population. In this study, we increased the sample size to investigate the modifying effect of lifetime alcohol consumption on the association between ADH1B and ALDH2 genotypes and the risks of esophageal cancer. A multicenter hospital-based case-control study was conducted between August 2000 and June 2004. Three hundred and thirty newly-diagnosed esophageal squamous cell carcinoma patients and 592 controls were recruited from National Taiwan University Hospital in Taipei and Kaohsiung Veterans General Hospital and Kaohsiung Medical University Hospital in Kaohsiung, Taiwan. Controls were matched to the case patients by gender and age within 4 years (case:control = 1:1-4). Polymorphisms of ADH1B and ALDH2 were genotyped by the method of PCR-RFLP. Individuals with ADH1B*1/*1 genotype had a 3.99-fold risk (95% CI = 2.13-7.48) of developing esophageal cancer, compared with those with ADH1B*2/*2 genotype, after adjusted for appropriate covariates. Individuals with ALDH2*1/*2 and ALDH2*2/*2 had 4.99-fold risk (95% CI = 3.11-7.99) and 4.24-fold risk (95% CI = 1.52-11.84), respectively, of developing esophageal cancer, compared with those with ALDH2*1/*1, after adjusted for appropriate covariates. We also found a modifying effect of lifetime alcoholic consumption on the association between genotypes of ADH1B and ALDH2 on esophageal cancer risk. These results suggest that ADH1B and ALDH2 polymorphisms play a pivotal role on esophageal cancer and that the effect of these polymorphisms was modified by the amount of alcohol consumed.

Cichoz-Lach H; Partycka J; Nesina I; Celinski K; Slomka M; Wojcierowski J. Alcohol dehydrogenase and aldehyde dehydrogenase gene polymorphism in alcohol liver cirrhosis and alcohol chronic pancreatitis among Polish individuals. Scandinavian Journal of Gastroenterology 42(4): 493-498, 2007. (40 refs.)

Objective. To investigate the effects of ADH and ALDH gene polymorphism on the development of alcoholism, alcohol liver cirrhosis and alcohol chronic pancreatitis among Polish individuals. Material and methods. We determined the allele and genotype of ADH2, ADH3 and ALDH2 in 198 subjects: 57 with alcohol cirrhosis, 44 with alcohol chronic pancreatitis and 43 "healthy alcoholics"; 54 healthy non-drinkers served as controls. Genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method on white cell DNA. Results. In the population examined the ADH2*1 allele frequency was 97.97%. The tests did not show the ADH2*3 allele. The ADH3*1 allele frequency was 57.07%. The ADH2*1 and the ADH3*1 alleles were statistically more common among patients who abuse alcohol in comparison with the controls. The ADH2*2 allele was not detected in any of the patients with chronic alcohol pancreatitis. The ADH2*1/*1 and the ADH3*1/*1 genotypes were statistically significantly more common among the patients who abuse alcohol than in the control group. All patients were ALDH2*1/*1 homozygotic. Patients with the ADH3*1 allele and the ADH3*1/*1 genotype started to abuse alcohol significantly earlier in comparison to the patients with the ADH3*2 allele and the ADH3*2/*2 genotype. Conclusions. In the Polish population examined, the ADH3*1 allele and the ADH3*1/*1 genotype are conducive to the development of alcoholism, alcohol liver cirrhosis and alcohol chronic pancreatitis. However, the ADH2*2 allele is likely to protect against these conditions. Genetic polymorphism of ALDH2 shows no correlation with alcohol addiction or alcohol cirrhosis and alcohol chronic pancreatitis. The ADH3*1 allele and the ADH3*1/*1 genotype are conducive to alcohol abuse starting at a younger age.

Clarimon J; Gray RR; Williams LN; Enoch MA; Robin RW; Albaugh B; Singleton A et al. Linkage disequilibrium and association analysis of alpha-synuclein and alcohol and drug dependence in two American Indian populations. Alcoholism: Clinical and Experimental Research 31(4): 546-554, 2007. (43 refs.)

Background: alpha-Synuclein is involved in dopaminergic neurotransmission and has been implicated in a number of neurodegenerative disorders, such as Parkinson's disease. Recent studies, in humans and in rat and monkey models, have suggested that alpha-synuclein may play a role in the development and maintenance of certain addictive disorders. Methods: Fifteen single-nucleotide polymorphisms (SNPs) in the alpha-synuclein gene (SNCA) and 1 upstream microsatellite repeat (NACP-REP1) were assayed in Southwest (SW; n=514) and Plains (n=420) American Indian populations. Patterns of linkage disequilibrium (LD) at SNCA were determined for the 2 populations and compared with Caucasian, African, and Asian populations in the HapMap database (http: www.hapmap.org). Assayed alleles and constructed haplotypes in the study populations were tested for association with 4 clinical phenotypes [alcohol dependence, alcohol use disorders, drug dependence, and drug use disorders (lifetime diagnoses)] as well as with 2 symptom count phenotypes (all 18 questions and the 8 questions diagnostic for alcohol dependence). Results: Patterns of LD at SNCA were similar in both Indian populations and were consistent with the LD structure in other populations as reflected in the HapMap database. Single allele tests revealed significant associations between 4 SNPs and drug dependence in the SW population and between 2 of those SNPs plus 2 other SNPs and drug dependence in SW males only. In the Plains population, a significant association was detected only in males between 2 SNPs and alcohol use disorders and between 1 SNP and alcohol dependence. In the SW population, 1 SNP was marginally significant with the total symptom count. However, in all cases, the support was modest and disappeared with correction for multiple comparisons. No association was found between constructed haplotypes and any of the phenotypes in either population. Conclusions: Despite modest support for association between multiple SNCA SNPs and several of the addictive disorders tested in this study, statistical significance disappeared after correction for multiple testing. Thus, our data do not support a role for a variant in the SNCA gene that contributes to alcohol or drug addiction in the 2 studied American Indian populations. Future research may focus on variants in the promoter region that could cause the changes in mRNA and protein levels observed in previous studies.

Cosci F; Schruers KRJ; Abrams K; Griez EJL. Alcohol use disorders and panic disorder: A review of the evidence of a direct relationship. (review). Journal of Clinical Psychiatry 68(6): 874-880, 2007. (39 refs.)

Objective: It is generally agreed that alcohol use disorders and panic disorder with (PD[A]) or without agoraphobia (PD) tend to occur within the same individual. However, the cause of this comorbidity remains controversial. Three main explanations are that (1) PD(A) promotes pathologic alcohol use as self-medication, (2) chronic alcohol use and alcohol withdrawal induce changes in the neurochemical system that promote panic, and (3) a third factor, such as familial transmission, promotes both conditions. The aim of this review was to survey the literature in order to determine the validity of these explanatory models. Data Sources: A review of epidemiologic, family, and laboratory studies was performed. Studies were identified using PubMed (English-language articles published from 1960 to 2006, using the search term alcohol and panic). Study Selection: Twenty studies were reviewed and selected according to the following criteria: PD(A) and alcohol abuse/dependence diagnosed according to the DSM, no additional comorbidity, use of adult samples, comparison with a nonclinical control group, or application of a crossover design. Data Extraction: Nonsignificant results or trends only were reported as "no difference." Data on "anxiety disorders" or "substance abuse" in general were not included. Data Synthesis: In PD(A), alcohol lessens anxious apprehension, thereby decreasing the likelihood of panic. In alcohol use disorders, alcohol increases CO2 sensitivity and may thereby promote panic. In both cases, a significant familial transmission contributes to the co-occurrence. Conclusion: Findings would seem to indicate that PD(A) and alcohol use disorders can both serve to initiate the other via independent mechanisms. Further studies are warranted.

Criado JR; Ehlers CL. Electrophysiological responses to affective stimuli in southwest California Indians: Relationship to alcohol dependence. Journal of Studies on Alcohol and Drugs 68(6): 813-823, 2007. (97 refs.)

Objective: Native Americans have some of the highest rates of alcohol abuse and dependence, yet potential risk factors associated with the problem drinking seen in some tribes remain relatively unknown. The present investigation evaluated associations between the P350 and P450 components of the event-related potential (ERP) elicited by affective stimuli and potential vulnerability factors associated with risk of alcohol dependence in Southwest California (SWC) Indian adults. Method: Data from 517 Native American SWC Indian adults between the ages of 18 and 70 were used in the analyses. ERPs were collected using a task that required discrimination among faces with neutral, sad, and happy facial expressions. Results: P450 amplitudes were significantly reduced in participants who met lifetime Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised, criteria for alcohol dependence in centroparietal leads. In contrast, participants who met personal lifetime criteria for affective disorder were found to have higher P350 and P450 amplitudes in frontal leads. Neither P350 nor P450 component amplitudes were significantly altered based on a family history of alcohol dependence, a personal history of antisocial personality disorder/conduct disorder, or the presence of drug dependence other than alcohol. Conclusions: These findings suggest, in this select population, that P450 amplitudes are selectively affected by both alcohol dependence and affective disorder. However, reductions in P450 amplitude were restricted to those participants with alcohol dependence, confirming that it may be an important putative endophenotype for genetic studies of that disorder in this high-risk population.

Dai X; Thavundayil J; Santella S; Gianoulakis C. Response of the HPA-axis to alcohol and stress as a function of alcohol dependence and family history of alcoholism. Psychoneuroendocrinology 32(3): 293-305, 2007. (78 refs.)

Dysfunction of the hypothalamic-pituitary-adrenal (HPA)-axis has been observed in chronic alcoholics and in non-alcoholic sons of alcoholic parents, while genetic and environmental factors, such as stress, may play a significant rote in the development of alcoholism. The present study was designed to investigate the response of the HPA-axis to alcohol and stress as a function of family history of alcoholism and chronic alcohol abuse. We determined changes in plasma adrenal corticotrophin (ACTH) and cortisol concentrations in response to a placebo or an alcohol (0.50 g ethanol/kg body wt) drink and to a stress task performed 30 min following ingestion of either the placebo or the alcohol drink in social and heavy drinkers with [high risk (HR)] and without [low risk (LR)] a family history of alcoholism. Thus, four groups of healthy mate individuals, low risk with no alcohol-dependence diagnosis (LRNAD), high risk with no alcohol-dependence diagnosis (HRNAD), low-risk alcohol dependent (LRAD) and high-risk alcohol dependent (HRAD), participated in the four experimental sessions given in random order. Basal plasma ACTH levels of LRNAD participants were higher from those of the other three groups of participants. Basal plasma cortisol levels of HRAD participants were higher from those of LRNAD and HRNAD but not of LRAD participants. The stress-induced increases of plasma ACTH and cortisol concentrations were more pronounced in LRNAD participants. The alcohol drink prevented the stress-induced increases in plasma ACTH and cortisol of all groups of participants. The self-ratings of anxiety were attenuated in LRNAD and LRAD participants in the alcohol only session and in HRNAD and HRAD participants in the alcohol plus stress session. In conclusion, there are differences in the activity of the HPA-axis as a function of family history and alcohol dependence, white the effect of an alcohol drink on the self-rating of anxiety may be influenced by both family history and stress.

Davis LL; Frazier EC; Gaynes BN; Trivedi MH; Wisniewski SR; Fava M et al. Are depressed outpatients with and without a family history of substance use disorder different? A baseline analysis of the STARD cohort. Journal of Clinical Psychiatry* 68(12): 1931-1938, 2007. (31 refs.)

Objective: This report compares the baseline demographic and clinical characteristics of outpatients with nonpsychotic major depressive disorder (MDD) and a family history of substance use disorder (SUD) versus those with MDD and no family history of SUD. Method: Using data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, we grouped participants with MDD (DSM-IV criteria) according to presence or absence of family history of SUD based on participant report. Between-group comparisons were made of demographic and clinical characteristics, depressive symptoms, and psychiatric comorbidities. Patients were enrolled from July 2001 until August 2004. Results: Of 4010 participants, 46% had a positive family history of SUD. Those with a positive family history were less likely to be Hispanic (p=.0029) and more likely to be female (p=.0013). They were less educated (p=.0120), less likely to be married (p <.01), and more likely to be divorced (p <.01). They also reported an earlier age at onset of MDD, greater length of illness, and more major depressive episodes (all p <.001). They had an increased likelihood of recurrent MDD, more prior suicide attempts, and more concurrent psychiatric comorbidities, including posttraumatic stress disorder, SUD, and generalized anxiety disorder (all p <.0001). Conclusion: Depressed patients with a family history of SUD had a more severe previous course of depression, were more likely to have attempted suicide, and had a greater burden of psychiatric comorbid conditions than patients without such a family history. These findings represent important clinical features to be considered in the evaluation and treatment planning of patients with MDD.

Davis TJ; de Fiebre CM. Alcohol's actions on neuronal nicotinic acetylcholine receptors. Alcohol Research and Health 29(3): 179-185, 2006. (31 refs.)

Although it has been known for many years that alcoholism and tobacco addiction often co-occur, relatively little information is available on the biological factors that regulate the co-use and abuse of nicotine and alcohol. In the brain, nicotine acts at several different types of receptors collectively known as nicotinic acetylcholine receptors (nAChRs). Alcohol also acts on at least some of these receptors, enhancing the function of some nAChR subtypes and inhibiting the activity of others. Chronic alcohol and nicotine administration also lead to changes in the numbers of nAChRs. Natural variations (i.e., polymorphisms) in the genes encoding different nAChR subunits may be associated with individual differences in the sensitivity to some of alcohol's and nicotine's effects. Finally, at least one subtype of nAChR may help protect cells against alcohol-induced neurotoxicity.

Dick DM. Identification of genes influencing a spectrum of externalizing psychopathology. Current Directions in Psychological Science 16(6): 331-335, 2007. (23 refs.)

Alcohol dependence, drug dependence, childhood conduct disorder, and adult antisocial behavior commonly occur in combination. Data from multiple literatures, including twin/family studies and electrophysiological studies, suggest that the overlap of these disorders is largely due to a shared genetic liability that contributes to a spectrum of externalizing psychopathology. These findings suggest that some genes will not be specific to any one externalizing disorder but will predispose individuals broadly to a spectrum of externalizing psychopathology. Here we review evidence for specific, identified genes, GABRA2 and CHRM2, that follow this pattern and confer risk for a spectrum of externalizing disorders. These findings confirm the etiological structure of psychopathology suggested by psychological research and suggest exciting new roles that psychologists can play in understanding the pathways underlying associations between genes and behavior.

Dick DM; Agrawal A; Wang JC; Hinrichs A; Bertelsen S; Bucholz KK et al. Alcohol dependence with comorbid drug dependence: Genetic and phenotypic associations suggest a more severe form of the disorder with stronger genetic contribution to risk. Addiction 102(7): 1131-1139, 2007. (46 refs.)

Background: Twin data suggest that alcohol dependence comorbid with illicit drug dependence represents a more heritable form of the disorder. In the Collaborative Study on the Genetics of Alcoholism sample, approximately half the alcohol-dependent individuals also meet diagnostic criteria for illicit drug dependence. In this study, we tested for heterogeneity in the association between the muscarinic acetylcholine M2 receptor gene (CHRM2) and alcohol dependence, reported previously in the full sample, among the subgroups of alcohol-dependent individuals with and without comorbid drug dependence. Methods Family-based association tests were conducted separately (a) in individuals with alcohol dependence with comorbid drug dependence (n = 477) and (b) in individuals with alcohol dependence without comorbid drug dependence (n = 433). These subgroups were subsequently compared on other phenotypic characteristics. Results The evidence for association between CHRM2 and alcohol dependence came entirely from the subgroup of individuals with comorbid drug dependence. There was no evidence of association with CHRM2 among the alcohol-dependent individuals without drug dependence. Subsequent phenotypic analyses suggest that the subgroup of alcohol-dependent individuals with comorbid drug dependence differ on a number of other phenotypic characteristics, including several measures of the severity of their alcohol problems, personality traits and comorbid psychiatric disorders. Conclusions: These analyses provide specific genetic evidence suggesting that alcohol dependence with comorbid drug dependence represents a particularly severe form of the disorder, with higher genetic contribution to vulnerability.

Dick DM; Pagan JL; Holliday C; Viken R; Pulkkinen L; Kaprio J et al. Gender differences in friends' influences on adolescent drinking: A genetic epidemiological study. Alcoholism: Clinical and Experimental Research 31(12): 2012-2019, 2007. (28 refs.)

Background: We use data from a population-based twin study to examine the association between characteristics of the friendship group and adolescents' own alcohol use at age 14, with focus on gender differences, both with respect to the adolescent's own gender and the gender composition of his/her friendship group. Methods: (1) We conducted analyses on the full epidemiological sample of individuals to determine the magnitude of association between friendship characteristics and alcohol use, and to test for interaction with gender and gender of friends. (2) We used the twin structure of the dataset to study the extent to which similarity in drinking behaviors between adolescents and their friends was due to shared genetic and/or environmental pathways. Results: Friends' drinking, smoking, and delinquency were more strongly related to alcohol use in girls, compared to boys, and in adolescents with opposite-sex friends, compared to adolescents with only same-sex friends. Friends' alcohol use showed modest evidence of genetic influence in girls, suggesting peer selection; however, there was no evidence of genetic influence on friends' alcohol use in boys. The correlation between adolescent and friend drinking was largely attributable to shared environmental effects across genders. Conclusion; Gender and gender of friends moderate the associations between friends' behavior and adolescents' alcohol use, with evidence that girls, and those with opposite-sex friends, may be more susceptible to friends' influence. Genetically informative analyses suggest that similarity in alcohol use between adolescents and their friends is mediated, at least partially, through environmental pathways.

Dick DM; Plunkett J; Hamlin D; Nurnberger J; Kuperman S; Schuckit M et al. Association analyses of the serotonin transporter gene with lifetime depression and alcohol dependence in the Collaborative Study on the Genetics of Alcoholism (COGA) sample. Psychiatric Genetics 17(1): 35-38, 2007. (46 refs.)

The objective of this study was to analyze association of the serotonin transporter gene 5-HTTLPR polymorphism on lifetime depression and alcohol dependence in the Collaborative Study on the Genetics of Alcoholism sample. We conducted family-based association analyses in 1913 Caucasians genotyped for the 5-HTTLPR polymorphism. We found evidence for association of the short allele with depression, but no evidence of association with alcohol dependence. On the basis of the evidence that the effect of this polymorphism may be moderated by stressful life events, we classified individuals for the presence and/or absence of stress, as defined by unemployment, relationship problems, or poor health. The evidence for the association with lifetime depression was limited to the group of individuals who had experienced stress, paralleling the direction of effects originally reported by Caspi and colleagues. No evidence was found for the association with alcohol dependence in either the stress or the no-stress groups.

Dodd PR; Buckley ST; Eckert AL; Foley PF; Innes DJ. Genes and gene expression in the brains of human alcoholics. Annals of the New York Academy of Sciences. Cellular and molecular mechanisms 1074: 104-115, 2006. (32 refs.)

Chronic alcohol misuse by human subjects leads to neuronal loss in regions such as the superior frontal cortex (SFC). Propensity to alcoholism is associated with several genes. gamma-Aminobutyric acid (GABA)A receptor expression differs between alcoholics and controls, whereas glutamate receptor differences are muted. We determined whether genotype differentiated the regional presentation of GABA(A) and glutamate-NMDA (N-methyl-D-aspartate) receptors in SFC. Autopsy tissue was obtained from alcoholics without comorbid disease, alcoholics with liver cirrhosis, and matched controls. ADH1C, DRD2B, EAAT2, and APOE genotypes modulated GABA(A)-beta subunit protein expression in SFC toward a less-effective form of the receptor. Most genotypes did not divide alcoholics and controls on glutamate-NMDA receptor pharmacology, although gender and cirrhosis did. Genotype may affect amino acid transmission locally to influence neuronal vulnerability.

Doran N; Myers MG; Luczak SE; Carr LG; Wall TL. Stability of heavy episodic drinking in Chinese- and Korean-American college students: Effects of ALDH2 gene status and behavioral undercontrol. Journal of Studies on Alcohol and Drugs 68(6): 789-797, 2007. (65 refs.)

Objective: A previous cross-sectional study showed that, among individuals of Chinese and Korean descent, possession of ALDH2*2 alleles was associated with protection against alcohol dependence, whereas conduct disorder was associated with increased vulnerability to dependence. The purpose of this longitudinal study was to examine the roles of ALDH2 and behavioral undercontrol (a temperamental trait that is associated with conduct disorder) in stability of heavy episodic drinking. Method: Chinese- and Korean-American college students (N= 336; 51% female), who had initiated alcohol use before study enrollment, provided information on drinking habits during their freshman and sophomore years. Participants were classified as (1) stable nonheavy drinkers, (2) regressors, (3) progressors, or (4) stable heavy drinkers. Results: Participants with ALDH2 *2 alleles were more likely to be classified as stable nonheavy drinkers than as progressors (z = -2.49, p =.0 13). Higher levels of behavioral undercontrol were associated with a greater probability of being classified as a stable heavy drinker relative to a stable nonheavy drinker (z = 2.26, p =.024). Stable heavy drinkers reported the most alcohol-related problems, whereas progressors reported more problems than either regressors or stable nonheavy drinkers, particularly at Year 2. Conclusions: Elevated behavioral undercontrol appears to predispose Asian-American college students to increased frequency of heavy drinking, whereas ALDH2*2 may act as a protective factor. The degree of alcohol consumption observed among participants with ALDH2*2 alleles is consistent with previous findings showing that, although their presence may be protective, it does not preclude heavy drinking episodes.

Drgon T; D'Addario C; Uhl GR. Linkage disequilibrium, haplotype and association studies of a chromosome 4 GABA receptor gene cluster: Candidate gene variants for addictions. American Journal of Medical Genetics, Part B. Neuropsychiatric Genetics 141B(8): 854-860, 2006. (35 refs.)

Strong genetic contributions to individual differences in vulnerability to addictions are well supported by classical genetic studies. Linkage and association genome scans for addiction vulnerability have provided converging evidence for several chromosomal regions which are likely to harbor allelic variants that contribute to such vulnerability. We and others have delineated a candidate addiction-associated chromosome 4p12 "rSA3" region based on convergent data from association genome scanning studies in polysubstance abusers [Uhl et al. (2001); Am J Hum Genet 69(6):1290-1300], linkage-based studies in alcoholism [Long et al. (1998); Am J Med Genet 81(3):216-221; Reich et al. (1998); Am J Med Genet 81(3):207-215] and association-based studies for alcoholism and association-based studies for individual differences in electroencephalographic (EEG) spectral power phenotypes [Porjesz et al. (2002); Proc Natl Acad Sci USA 99(6):3729-3733; Edenberg et al. (2004); Am J Hum Genet 74(4): 705-714]. The rSA3 region contains interesting candidate genes that encode the alpha 2, alpha 4, beta 1, and gamma 1 receptor subunits for the principal brain inhibitory neurotransmitter, gamma-aminobutyric acid (GABA) [Covault et al. (2004); Am J Med Genet Part B 129B:104-109; Edenberg et al. (2004); Am J Hum Genet 74(4):705-714; Lappalainen et al. (2005); Alcohol Clin Exp Res 29(4):493-498]. We now report assessment of single nucleotide polymorphism (SNP) genotypes in this region in three samples of substance abusers and controls. These results delineate the haplotypes and patterns of linkage disequilibrium in this region, focus attention of the GABRA2 gene and identify modest associations between GABRA2 genotypes and addiction phenotypes. These results are consistent with modest roles for GABRA2 variants in addiction vulnerabilities.

Ehlers CL; Phillips E. Association of EEG alpha variants and alpha power with alcohol dependence in Mexican American young adults. Alcohol 41(1): 13-20, 2007. (65 refs.)

Several studies support an association between electroencephalogram (EEG) voltage and alcohol dependence. However, the distribution of EEG variants also appears to differ depending on an individual's ethnic heritage, suggesting significant genetic stratification of this EEG phenotype. The present study's aims were to investigate the incidence of EEG alpha variants and spectral power in the alpha frequency range in Mexican American young adults based on gender, and personal and family history of alcohol dependence. Clinical ratings (high-, medium-, and low alpha voltage variants) and spectral characteristics of the EEG in the alpha frequency range (7.5-12 Hz) were investigated in young adult (age 18-25 years) Mexican American men (n = 98) and women (n = 138) who were recruited from the community. Nineteen percent (n = 45) of the participants had a low-voltage alpha EEG variant, 18% had a high-voltage variant, and 63% had a medium-voltage variant. There were no significant differences in the distribution of the EEG variants based on family history of alcohol dependence. There was a significant relationship between gender and the three alpha variants (chi(2) = 9.7; df = 2; P <.008), and there were no male participants with alcohol dependence with high alpha variants (chi(2) = 5.8; df = 2; P <.056). Alcohol dependence, but not a family history of alcohol dependence, was associated with lower spectral power in the alpha frequency range in the right (F = 4.4; df = 1,96; P <.04) and left (F = 5.3; df = 1.96; P <.02) occipital areas in the men but not in the women. In conclusion, in this select population of Mexican American young adults, male gender and alcohol dependence are associated with an absence of high-voltage alpha variants and lower alpha power in the EEG. These data suggest that EEG low voltage, a highly heritable trait, may represent an important endo-phenotype in male Mexican Americans that may aid in linking brain function with genetic factors underlying alcohol dependence in this ethnic group.

Enoch MA. Genetic and environmental influences on the development of alcoholism: Resilience vs. risk. Annals of the New York Academy of Sciences: Resilience in Children 1094: 193-201, 2006. (41 refs.)

The physiological changes of adolescence may promote risk-taking behaviors, including binge drinking. Approximately 40% of alcoholics were already drinking heavily in late adolescence. Most cases of alcoholism are established by the age of 30 years with the peak prevalence at 18-23 years of age. Therefore the key time frame for the development, and prevention, of alcoholism lies in adolescence and young adulthood. Severe childhood stressors have been associated with increased vulnerability to addiction, however, not all stress-exposed children go on to develop alcoholism. Origins of resilience can be both genetic (variation in alcohol-metabolizing genes, increased susceptibility to alcohol's sedative effects) and environmental (lack of alcohol availability, positive peer and parental support). Genetic vulnerability is likely to be conferred by multiple genes of small to modest effects, possibly only apparent in gene-environment interactions. For example, it has been shown that childhood maltreatment interacts with a monoamine oxidase A (MAOA) gene variant to predict antisocial behavior that is often associated with alcoholism, and an interaction between early life stress and a serotonin transporter promoter variant predicts alcohol abuse in nonhuman primates and depression in humans. In addition, a common Met158 variant in the catechol-O-methyltransferase (COMT) gene can confer both risk and resilience to alcoholism in different drinking environments. It is likely that a complex mix of gene(s)-environment(s) interactions underlie addiction vulnerability and development. Risk-resilience factors can best be determined in longitudinal studies, preferably starting during pregnancy. This kind of research is important for planning future measures to prevent harmful drinking in adolescence.

Faraone SV; Adamson JJ; Wilens TE; Monuteaux MC; Biederman J. Deriving phenotypes for molecular genetic studies of substance use disorders: A family study approach. Drug and Alcohol Dependence 88(2/3): 244-250, 2007. (51 refs.)

Although, family, twin, and adoption studies indicate that genes play a significant etiologic role in the development of substance use disorders (SUDs), the specific genes involved have been difficult to detect due, in part, to uncertainties about how best to define SUDs, the possibility of genetic heterogeneity and the variable phenotypic expression of SUD genotypes. The goal of the present work was to determine if phenotypes external to the diagnosis of SUD such as psychopathology and cognitive functioning would show evidence of utility as phenotypes for genetic studies of SUD. We did this by applying factor analysis to multiple measures collected from our family-study program and then determining if these factors were heritable and were co-familial with SUDs. We used data from families recruited into six contemporaneous studies of four psychiatric conditions in children and adults. We found evidence for two SUD related phenotypes. One was an index of Psychopathology and Psychosocial Impairment; the other was an index of school failure and cognitive dysfunction. Both factors showed evidence of heritability, longitudinal stability and familial association with Parental SUD but these findings were stronger for the index of school failure and cognitive dysfunction. Results provide some support for the idea that candidate SUD phenotypes such as psychopathology and cognitive functioning, which are external to the diagnostic criteria for SUDs, may be useful for genetic studies of SUD.

Fowler T; Lifford K; Shelton K; Rice F; Thapar A; Neale MC et al. Exploring the relationship between genetic and environmental influences on initiation and progression of substance use. Addiction 102(3): 413-422, 2007. (43 refs.)

Aims: To examine the genetic and environmental contributions to the initiation of use and progression to more serious use of alcohol, cigarettes and marijuana during adolescence, and to examine the relationship between initiation and progression of substance use. Design: The study used a twin-based design and a new theoretical model, the causal-common-contingent (CCC) model. This allows modelling of the relationship between initiation of use and progression to heavier use as a two-stage model and the examination of genetic and environmental influences on both stages, while taking into account their relationship. Participants: The participants consisted of 1214 twin pairs (69% response rate) aged 11-19 years sampled from the UK population-based Cardiff Study of AllWales and North-west of England Twins (CaStANET). Measurements: Data on adolescent initiation and progression to more serious use of alcohol, cigarettes and marijuana were obtained using self-report questionnaires. Findings: Initiation of alcohol and progression to heavier alcohol use had separate but related underlying aetiologies. For cigarette and marijuana use the relation between initiation and progression to heavier use was stronger, suggesting greater overlap in aetiologies. For all three substances, environmental influences that make twins more similar (common environment) tended to be greater for initiation, while genetic influences were stronger for heavier use. Conclusions These findings have implications for policy decisions aimed at an adolescent and early adult age group. Specifically, these findings suggest that it may be more efficacious to focus alcohol interventions on risk factors for the development of heavier use rather than initiation of use. In contrast, interventions aimed at reducing the initiation of cigarettes and marijuana use may be more appropriate.

Fowler T; Shelton K; Lifford K; Rice F; McBride A; Nikolov I. Genetic and environmental influences on the relationship between peer alcohol use and own alcohol use in adolescents. Addiction 102(6): 894-903, 2007. (48 refs.)

Aims: Genetically influenced aspects of adolescent behaviour can play a role in alcohol use and peer affiliation. We explored the correlations between friends' alcohol use and adolescent own use with a genetically sensitive design. Design: Genetic and environmental factors were estimated on adolescent reports of their friends' alcohol use and their own use and problem use of alcohol. The correlations between the genetic and environmental factors that influence friends' alcohol use and adolescent own alcohol use and problem use were also estimated. Participants: A total of 862 twin pairs aged 11-17 years sampled from the UK population-based Cardiff Study of All Wales and North-west of England Twins (CaStANET). Measurments: Data on adolescent own alcohol use and problem use and the alcohol use of their three best friends were obtained using self-report questionnaires. Findings: A significant genetic influence was found on adolescent friends' alcohol use (about 30%). Significant correlations of 0.60 and 0.70 were found between the genetic influences on friends' alcohol use and adolescents' own use and problem use of alcohol. Common environmental influences were almost completely correlated for friends' alcohol use and adolescents' own alcohol use and problem use (0.91 and 0.94). Conclusions: There is considerable overlap in the common environmental and genetic factors that contribute to the relationship between adolescents' own alcohol use and that of their friends. These findings contribute to understanding of the mechanisms by which friends' alcohol use influences adolescent drinking behaviour.

Gao CM; Takezaki T; Wu JZ; Chen MB; Liu YT; Ding IH et al. CP2E1 Rsa I polymorphism impacts on risks of colorectal cancer association with smoking and alcohol drinking. World Journal of Gastroenterology 13(43): 5725-5730, 2007. (44 refs.)

AIM: To investigate associations between the Rsa I polymorphism of CYP2E1 and risk of colorectal cancer. METHODS: A case-control study was conducted with 315 colorectal cancer cases (105 colon, 210 rectal) and 439 population-based controls in Jiangsu Province of China. Genomic DNA samples were assayed for restriction fragment length polymorphisms in CYP2E1 by PCR amplification followed by digestion with Rsa I. Information on smoking and alcohol drinking was collected using a questionnaire. Odds ratios (ORs) were estimated with an unconditional logistic model. RESULTS: The proportional distribution of the CYP2E1 Rsa I cl/cl, c1/c2 and c2/c2 genotypes were 61.4%, 35.6% and 3.0% in controls, 60.6%, 33.7% and 5.8% in colon cancer cases, and 58.4%, 34.0% and 7.7% in rectal cancer cases, respectively. A significant difference was noted between controls and rectal cancer cases (P = 0.029), the c2/c2 genotype being associated with elevated OR (adjusted age, sex and status of the smoking and alcohol drinking) for rectal cancer (1.64, 95% CI, 1.12-2.41, vs cl allele carriers), but not for colon cancer. In interaction analysis between the CYP2E1 Rsa I genotype and smoking and drinking habits, we found a significant cooperative action between the c2/c2 genotype and alcohol drinking in the sex-, age-adjusted ORs for both colon (4.74, 95% CI, 1.10-20.40) and rectal (5.75, 95% CI, 1.65-20.05) cancers. Among nonsmokers, the CYP2E1 Rsa I c2/c2 genotype was also associated with elevated ORs in the two sites (1.95, 95% CI, 0.99-3.86 and 2.30, 95% CI, 1.32-3.99). CONCLUSION: The results of the present study suggest that the CYP2E1 c2/c2 genotype increases susceptibility to rectal cancer and the gene-environmental interactions between the CYP2E1 polymorphism and smoking or alcohol drinking exist for colorectal neoplasia in general.

Gass JT; Olive MF. Glutamatergic substrates of drug addiction and alcoholism. (review). Biochemical Pharmacology 75(1): 218-265, 2008. (906 refs.)

The past two decades have witnessed a dramatic accumulation of evidence indicating that the excitatory amino acid glutamate plays an important role in drug addiction and alcoholism. The purpose of this review is to summarize findings on glutamatergic substrates of addiction, surveying data from both human and animal studies. The effects of various drugs of abuse on glutamatergic neurotransmission are discussed, as are the effects of pharmacological or genetic manipulation of various components of glutamate transmission on drug reinforcement, conditioned reward, extinction, and relapse-like behavior. In addition, glutamatergic agents that are currently in use or are undergoing testing in clinical trials for the treatment of addiction are discussed, including acamprosate, N-acetylcysteine, modafinil, topiramate, lamotrigine, gabapentin and memantine. All drugs of abuse appear to modulate glutamatergic transmission, albeit by different mechanisms, and this modulation of glutamate transmission is believed to result in long-lasting neuroplastic changes in the brain that may contribute to the perseveration of drug-seeking behavior and drug-associated memories. In general, attenuation of glutamatergic transmission reduces drug reward, reinforcement, and relapse-like behavior. On the other hand, potentiation of glutamatergic transmission appears to facilitate the extinction of drug-seeking behavior. However, attempts at identifying genetic polymorphisms in components of glutamate transmission in humans have yielded only a limited number of candidate genes that may serve as risk factors for the development of addiction. Nonetheless, manipulation of glutamatergic neurotransmission appears to be a promising avenue of research in developing improved therapeutic agents for the treatment of drug addiction and alcoholism.

Gelernter J; Gueorguieva R; Kranzler HR; Zhang HP; Cramer J; Rosenheck R; VA Study Group. Opioid receptor gene (OPRM1, OPRK1, and OPRD1) variants and response to naltrexone treatment for alcohol dependence: Results from the VA cooperative study. Alcoholism: Clinical and Experimental Research 31(4): 555-563, 2007. (39 refs.)

Background: Pharmacotherapy of alcohol dependence (AD) is at an early stage of development; currently available medications have limited efficacy. It would be clinically valuable to identify, before initiation of a course of treatment, those patients who, based on genetic markers, are most likely to respond to a specific pharmacotherapy. A previous report suggested that a functional variant at the genetic locus encoding the mu opioid receptor (Asn40Asp) is such a marker, in short-term (3-month) treatment with the opioid-blocking drug naltrexone (NTX). Methods: We studied polymorphic variants at each of the 3 opioid receptor genes-OPRM1, OPRD1, and OPRK1, which encode the mu, delta, and kappa opioid receptors, respectively-including the OPRM1 Asn40Asp variant-as predictors of response to NTX or placebo in 215 alcohol-dependent male subjects who participated in Veterans Affairs Cooperative Study 425, "Naltrexone in the Treatment of Alcohol Dependence." Results: At the 3-month time point, treatment condition, age, and the pretreatment number of drinks per drinking day were all significant (p < 0.05) predictors of the rate of relapse and time to relapse. Although NTX had no significant effect on relapse to heavy drinking in the overall sample in CSP 425, it significantly reduced relapse in the subgroup that provided DNA for analysis (i.e., the present study sample). There were no significant interactions between any individual single nucleotide polymorphisms studied and NTX treatment response. Conclusions: These results do not support association of the OPRM1 Asn40Asp polymorphism with NTX treatment response for AD.

Gemma S; Vichi S; Testai E. Metabolic and genetic factors contributing to alcohol induced effects and fetal alcohol syndrome. (review). Neuroscience and Biobehavioral Reviews 31(2): 221-229, 2007. (53 refs.)

Alcohol-related damages on newborns and infants include a wide variety of complications from facial anomalies to neurodevelopmental delay, known as fetal alcohol syndrome (FAS). However, only less than 10% of women drinking alcohol during pregnancy have children with FAS. Understanding the risk factors increasing the probability for newborn exposed in utero to alcohol to develop FAS is therefore a key issue. The involvement of genetics as a one risk factor in FAS has been suggested by animal models and by molecular epidemiological studies on different populations, bearing allelic variants for those enzymes, such as ADH e CYP2E1, involved in ethanol metabolism. Indeed, one of the major factors determining the peak blood alcohol exposure to the fetus is the metabolic activity of the mother, in addition to placental and fetal metabolism, explaining, at least partially, the risk of FAS. The different rates of ethanol metabolism may be the result of genetic polymorphisms, the most relevant of which have been described in the paper.

Goodman A. Neurobiology of addiction - An integrative review. (review). Biochemical Pharmacology 75(1): 266-322, 2008. (1118 refs.)

Evidence that psychoactive substance use disorders, bulimia nervosa, pathological gambling, and sexual addiction share an underlying biopsychological process is summarized. Definitions are offered for addiction and addictive process, the latter being the proposed designation for the underlying biopsychological process that addictive disorders are hypothesized to share. The addictive process is introduced as an interaction of impairments in three functional systems: motivation-reward, affect regulation, and behavioral inhibition. An integrative review of the literature that addresses the neurobiology of addiction is then presented, organized according to the three functional systems that constitute the addictive process. The review is directed toward identifying candidate neurochemical substrates for the impairments in motivation-reward, affect regulation, and behavioral inhibition that could contribute to an addictive process.

Grucza RA; Bierut LJ. Co-occurring risk factors for alcohol dependence and habitual smoking: Update on findings from the Collaborative Study on the Genetics of Alcoholism. Alcohol Research and Health 29(3): 172-178, 2006. (30 refs.)

Habitual smoking and alcohol dependence frequently co-occur, and the genetic factors that influence both conditions appear to overlap. The Collaborative Study on the Genetics of Alcoholism (COGA) has investigated genetic factors that contribute to both alcohol dependence and habitual smoking. Using a sample of families densely affected with alcohol dependence, COGA investigators have identified regions of the genome likely to contain genes that specifically contribute to alcohol dependence and habitual smoking, as well as regions likely to contain genes that contribute to the development of both conditions. Further genetic analyses (i.e., candidate gene studies) have helped identify specific genes that may contribute to the development of alcohol dependence and habitual smoking. These analyses have implicated several genes that encode parts of receptors for the neurotransmitter gamma-aminobutyric acid (GABA) in the development of alcohol or nicotine dependence, respectively. Other studies have identified additional candidate genes for alcohol or nicotine dependence. The results to date suggest that both common and drug-specific genetic influences play a role in the development of alcohol and nicotine dependence.

Public Domain

Guerrini I; Thomson AD; Gurling HD. The importance of alcohol misuse, malnutrition and genetic susceptibility on brain growth and plasticity. (review). Neuroscience and Biobehavioral Reviews 31(2): 212-220, 2007. (124 refs.)

The "dyad: alcoholic mother and foetus" is a very complex entity in which several elements such as genes, metabolism, diet, drugs and social habits play a role at different stages in the development of the fetal brain damage. The literature on the effects of alcohol consumption on the developing brain is extensive but very few evidences have been reported regarding the combined neurotoxic effects of poor nutrition and alcohol consumption. The consequences of ethanol intake alone or combined with poor maternal nutrition appear to be severe and life-long. Alcohol exerts its neurotoxic effects on the developing brain directly by acting on fetal brain tissues, and indirectly either by interfering with placental physiology or by impairing the mother's physiology. Alcohol misuse in pregnancy is also frequently associated with other conditions that can potentially increase the brain damage such as poor nutrition and smoking. This article reviews the effects of poor nutrition and alcohol misuse during pregnancy on the development of the fetal brain and discusses the cumulative effects of these two environmental factors and their interaction with maternal and fetal genetic make-ups.

Guo G; Wilhelmsen K; Hamilton N. Gene-lifecourse interaction for alcohol consumption in adolescence and young adulthood: Five monoamine genes. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 144B(4): 417-423, 2007. (61 refs.)

Association analysis has suggested that common sequence variants of genes that affect monoamine function can affect substance use and abuse. Demonstration of these associations has been inconsistent because of limited sample sizes and phenotype definition. Drawing on the life course perspective, we predicted a stronger association between the polymorphisms in 5HTT, DAT1, DRD4, DRD2, and MAOA and alcohol consumption in young adulthood than adolescence. This analysis tested for the gene-lifecourse interaction for the frequency of alcohol consumption in a nationally representative non-alcohol-dependent sample of 2,466 individuals that were visited during adolescence and young adulthood for four times between 1994 and 2002. All five genes are significantly associated with the frequency of alcohol consumption, with the genotype effects ranging 7%-20% of the mean score of alcohol consumption and their P values being 0.014, 0.0003, 0.003, 0.007, 0.005, and 0.003, respectively. The association is only observed in the life stage of young adulthood and not in adolescence. This analysis has demonstrated the potential usefulness of the life course perspective in genetic studies of human behaviors such as alcohol consumption.

Haberstick BC; Timberlake D; Smolen A; Sakai JT; Hopfer CJ; Corley RP et al. Between- and within-family association test of the dopamine receptor D2 TaqIA polymorphism and alcohol abuse and dependence in a general population sample of adults. Journal of Studies on Alcohol and Drugs 68(3): 362-370, 2007. (66 refs.)

Objective: Dopaminergic dysfunction has been hypothesized to play an important role in the etiology of alcohol-use disorders. A restriction fragment length polymorphism (RFLP) in the 3' untranslated region (3'UTR) of the DRD2 gene affects gene expression and has been implicated as a risk factor for alcohol dependence. This polymorphism (TaqIA) has been reported as positively associated with alcohol-use disorders in case-control samples, but these results have not been replicated in family-based association studies. The mixed results of association between the DRD2 TaqIA polymorphism and alcohol-use disorders may be the result of differences in sample size, phenotype definition, heterogeneity of the samples, and genetic admixture. Method: We conducted tests of association in a sample of 838 adults participating in the National Youth Survey Family Study (NYSFS). We examined whether the DRD2 TaqIA polymorphism was associated with a symptom-count measure of alcohol abuse and dependence derived from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and the Craving Withdrawal Model. Results: Tests of association were nonsignificant across each classification system examined. Power calculations suggested that these results were despite the ability to detect an effect size of 1%. Conclusions: This study supports other family-based association tests that have reported no association between the DRD2 TaqIA polymorphism and alcohol abuse and dependence.

Harris KM; Halpern CT; Smolen A; Haberstick BC. The National Longitudinal Study of Adolescent Health twin data. Twin Research and Human Genetics 9(6): 988-997, 2006. (23 refs.)

This article describes the design and data availability for samples of genetic pairs in the National Longitudinal Study of Adolescent Health (Add Health). Add Health provides unique samples of genetic pairs that are nationally representative and followed longitudinally from early adolescence into young adulthood with 3 in-home interviews and a 4th interview planned for 2007 to 2008. The design of Add Health included an embedded genetic sample of more than 3000 pairs of individuals with varying genetic resemblance, including monozygotic twins, dizygotic twins, full siblings, half siblings, and unrelated siblings who were raised in the same household. Add Health has collected rich longitudinal social, behavioral, and environmental survey data, as well as buccal cell DNA from a subsample of the genetic sample (N = 2612). Add Health has an enlightened dissemination policy and to date has released phenotype and genotype data to more than 3000 researchers in the scientific community.

Heilig M. IMAGEN: Implications for addiction science and science policy. (editorial). Addiction 102(11): 1699-1700, 2007. (19 refs.)

This is a commentary on an article in this issue on efforts to undertand genetic basis of substance abuse, how this is manifested in an individual's neurobiological functioing, which can be useful in tailoring specific treatments. IMAGEN is a collaborative effort being undertaken in Europe to explore this approach.

Heinz A; Friedel E; Muller DJ; Puls I; Wrase J. Genetic research with intermediate phenotypes: Phenocopies, perspectives and pitfalls. (editorial). Addiction 102(11): 1696-1697, 2007. (18 refs.)

This is a commentary on an article in this issue on efforts to undertand genetic basis of substance abuse, how this is manifested in an individual's neurobiological functioing, which can be useful in tailoring specific treatments. The nature of the research required and its challenges is outlined.

Hill SY; Kostelnik B; Holmes B; Goradia D; McDermott M; Diwadkar V et al. FMRI BOLD response to the eyes task in offspring from multiplex alcohol dependence families. Alcoholism: Clinical and Experimental Research 31(12): 2028-2035, 2007. (37 refs.)

Background: Increased susceptibility for developing alcohol dependence (AD) may be related to structural and functional differences in brain circuits that influence social cognition and more specifically, theory of mind (ToM). Alcohol dependent individuals have a greater likelihood of having deficits in social skills and greater social alienation. These characteristics may be related to inherited differences in the neuroanatomical network that comprises the social brain. Methods: Adolescent/young adult participants from multiplex AD families and controls (n = 16) were matched for gender, age, IQ, education, and handedness and administered the Eyes Task of Baron-Cohen during functional magnetic resonance imaging (fMRI). Results: High-risk (HR) subjects showed significantly diminished blood oxygen level dependent (BOLD) response in comparison with low-risk control young adults in the right middle temporal gyrus (RMTG) and the left inferior frontal gyrus (LIFG), areas that have previously been implicated in ToM tasks. Conclusions: Offspring from multiplex families for AD may manifest one aspect of their genetic susceptibility by having a diminished BOLD response in brain regions associated with performance of ToM tasks. These results suggest that those at risk for developing AD may have reduced ability to empathize with others' state of mind, possibly resulting in diminished social skill.

Hill SY; Muddasani S; Prasad K; Nutche J; Steinhauer SR; Scanlon J et al. Cerebellar volume in offspring from multiplex alcohol dependence families. Biological Psychiatry 61(1): 41-47, 2007. (58 refs.)

Background: Increased susceptibility for developing alcohol dependence (AD) might be related to structural differences in brain circuits that influence the salience of rewards and/or modify the efficiency of information processing. The role of the cerebellum in regulating cognitive functions is being increasingly recognized along with its well-known influence on motor performance. Additionally, developmental changes in cerebellar volume during adolescence have been reported. Methods: Magnetic resonance imaging was used to measure the cerebellum in 17 high-risk adolescent and young adult offspring from multiplex alcohol dependence families and 16 control subjects matched for gender, age, and IQ. Results: High-risk (HR) adolescents/young adults showed increased total cerebellum volume and total grey in comparison with control subjects. Age-related decreases in total grey volume were seen with age, a pattern that was not seen in HR offspring. Conclusions: Offspring from multiplex families for AD manifest genetic susceptibility by having larger cerebellar volume, which seems to be related to lesser grey matter pruning for age. Larger cerebellar volumes in adult obsessive compulsive disorder (OCD) patients have been reported. This suggests a possible similarity in structural underpinnings for alcohol dependence and OCD.

Hillemacher T; Wilhelm J; von Ahsen N; Bayerlein K; Frieling H; Kornhuber J et al. Obsessive-compulsive alcohol craving is not associated with Apolipoprotein E genotype. Psychiatric Genetics 16(6): 231-232, 2006. (4 refs.)

This study examined a possible association with obsessive and compulsive alcohol craving in 192 alcohol-dependent patients undergoing detoxification treatment. Statistical analysis revealed no significant association between Apolipoprotein E polymorphism and obsessive-compulsive alcohol craving (analysis of variance: F = 1.11, P = 0.358).

Hiraki A; Matsuo K; Wakai K; Suzuki T; Hasegawa Y; Tajima K. Gene-gene and gene-environment interactions between alcohol drinking habit and polymorphisms in alcohol-metabolizing enzyme genes and the risk of head and neck cancer in Japan. Cancer Science 98(7): 1087-1091, 2007. (22 refs.)

Alcohol consumption is a strong risk factor for squamous cell carcinoma of the head and neck (SCCHN). The genetic polymorphisms aldehyde dehydrogenase2 (ALDH2) Glu487Lys and alcohol dehydrogenase 2 (ADH2) His47Arg, which have a strong impact on alcohol metabolism, are common in the Japanese population. To clarify the significance of these polymorphisms in SCCHN carcinogenesis, we conducted a matched case-control study with 239 incident SCCHN subjects and 716 non-cancer controls. Both ADH2 Arg/Arg and ALDH2 Glu/Lys were found to be independently associated with increased risk, with odds ratios (OR) of 2.67 (95% confidence interval [CI] 1.51-4.57) and 1.66 (95% CI 1.20-2.31), respectively. Further, compared with subjects having both ADH2 His/His and ALDH2 Glu/Glu, the adjusted OR and its 95% CI for those with both ADH2 Arg/Arg and ALDH2 Glu/Lys was 5.00 (2.32-10.71) in all subjects. This combination effect was evident in heavy drinkers (OR 11.3, 95% CI 2.97-43.3) but not in moderate or non-drinkers. Statistically significant gene-environment interactions between the two polymorphisms and drinking level were seen (ADH2 P = 0.035, ALDH2, P = 0.013). Furthermore, we also found a statistically significant gene-gene interaction between the two polymorphisms (P = 0.042). In conclusion, this case-control study showed a significantly increased risk of SCCHN in subjects with the ADH2 Arg/Arg and ALDH2 Glu/Lys polymorphisms in a Japanese population. In addition, our results also demonstrated that this risk was associated with significant gene-gene interactions between ADH2 and ALDH2 polymorphisms, as well as gene-environment interactions between these polymorphisms and alcohol drinking.

Hopfer C. Study boosts evidence on linkage regions associated with alcoholism. (editorial). European Journal of Human Genetics 14(12): 1231-1232, 2006. (10 refs.)

Howell LL; Kimmel HL. Monoamine transporters and psychostimulant addiction. (review). Biochemical Pharmacology 75(1): 196-217, 2008. (355 refs.)

Psycho stimulants are a broadly defined class of drugs that stimulate the central and peripheral nervous systems as their primary pharmacological effect. The abuse liability of psychostimulants is well established and represents a significant public health concern. An extensive literature documents the critical importance of monoamines (dopamine, serotonin and norepinephrine) in the behavioral pharmacology and addictive properties of psychostimulants. In particular, the dopamine transporter plays a primary role in the reinforcing and behavioral-stimulant effects of psychostimulants in animals and humans. Moreover, both serotonin and norepinephrine systems can reliably modulate the neurochemical and behavioral effects of psychostimulants. However, there is a growing body of evidence that highlights complex interactions among additional neurotransmitter systems. Cortical glutamatergic systems provide important regulation of dopamine function, and inhibitory amino acid gamma-aminobutyric acid (GABA) systems can modulate basal dopamine and glutamate release. Repeated exposure to psychostimulants can lead to robust and enduring changes in neurobiological substrates, including monoamines, and corresponding changes in sensitivity to acute drug effects on neurochemistry and behavior. Significant advances in the understanding of neurobiological mechanisms underlying psychostimulant abuse and dependence have guided pharmacological treatment strategies to improve clinical outcome. in particular, functional agonist treatments may be used effectively to stabilize monoamine neurochemistry, influence behavior and lead to long-term abstinence. However, additional clinical studies are required in order to identify safe and efficacious pharmacotherapies.

Jensen MK; Mukamal KJ; Overvad K; Rimm EB. Alcohol consumption, TaqIB polymorphism of cholesteryl ester transfer protein, high-density lipoprotein cholesterol, and risk of coronary heart disease in men and women. European Heart Journal 29(1): 104-112, 2008. (45 refs.)

Aims: To investigate whether a common polymorphism in the cholesteryl ester transfer protein (CETP) gene modifies the relationship of alcohol intake with high-density lipoprotein cholesterol (HDL-C) and risk of coronary heart disease (CHD). Methods and results: Parallel nested case-control studies among women [Nurses' Health Study (NHS)] and men [Health Professionals Follow-up Study (HPFS)] where 246 women and 259 men who developed incident CHD were matched to controls (1:2) on age and smoking. The TaqIB variant and alcohol consumption were associated with higher HDL-C, with the most pronounced effects of alcohol among B2 carriers. In the NHS we did not find an inverse association between alcohol and CHD in B2 non-carriers (P trend: 0.5), but did among B2 carriers (P trend < 0.01). Among non-carriers the odds ratio (OR) for CHD among women with an intake of 5-14 g/day was 1.4 (95% CI: 0.6-3.7) compared with non-drinkers, whereas among B2 carriers the OR was 0.4 (0.2-0.8). Results in men were less suggestive of an interaction; corresponding OR's were 1.9 (0.8-4.5) and 0.9 (0.5-1.6), for B2 non-carriers and carriers, respectively. Conclusions: The association of alcohol with HDL-C levels was modified by CETP TaqIB2 carrier status, and there was also a suggestion of a gene-environment interaction on the risk of CHD.

Johnson C; Drgon T; Liu QR; Walther D; Edenberg H; Rice J et al. Pooled association genome scanning for alcohol dependence using 104,268 SNPs: Validation and use to identify alcoholism vulnerability loci in unrelated individuals from the Collaborative Study on the Genetics of Alcoholism. American Journal of Medical Genetics, Part B. Neuropsychiatric Genetics 141B(8): 844-853, 2006. (44 refs.)

Association genome scanning can identify markers for the allelic variants that contribute to vulnerability to complex disorders, including alcohol dependence. To improve the power and feasibility of this approach, we report validation of "100k" microarray-based allelic frequency assessments in pooled DNA samples. We then use this approach with unrelated alcohol-dependent versus control individuals sampled from pedigrees collected by the Collaborative Study on the Genetics of Alcoholism (COGA). Allele frequency differences between alcohol-dependent and control individuals are assessed in quadruplicate at 104,268 autosomal SNPs in pooled samples. One hundred eighty-eight SNPs provide (1) the largest allele frequency differences between dependent versus control individuals; (2) t values >= 3 for these differences; and (3) clustering, so that 51 relatively small chromosomal regions contain at least three SNPs that satisfy criteria 1 and 2 above (Monte Carlo P = 0.00034). These positive SNP clusters nominate interesting genes whose products are implicated in cellular signaling, gene regulation, development, "cell adhesion," and Mendelian disorders. The results converge with linkage and association results for alcohol and other addictive phenotypes. The data support polygenic contributions to vulnerability to alcohol dependence. These SNPs provide new tools to aid the understanding, prevention, and treatment of alcohol abuse and dependence.

Kaufman J; Yang BZ; Douglas-Palumberi H; Crouse-Artus M; Lipschitz D; Krystal JH et al. Genetic and environmental predictors of early alcohol use. Biological Psychiatry 61(11): 1228-1234, 2007. (47 refs.)

Background: The goal of the current investigation was to examine genetic and environmental predictors of early alcohol use, a potent predictor of later alcohol dependence. Methods: This study represents an add-on project to an investigation examining the efficacy of an intervention for maltreated children entering out-of-home care. Predictors of early alcohol use include the following: maltreatment, family loading for alcohol or substance-use disorders, and serotonin transporter genotype (5-HTTLPR; locus SLC6A4). Participants included 127 subjects: 76 maltreated children and 51 demographically matched community controls. Results: At follow-up, 29% of the maltreated children reported alcohol use, a rate more than seven times the rate observed in controls. Maltreated children also drank alcohol, on average, more than 2 years earlier than controls (11.2 vs. 13.5 years). Early alcohol use was predicted by maltreatment, 5-HTTLPR, and a gene by environment interaction, with increased risk for early alcohol use associated with the s-allele. Psychopathology at baseline, severity of maltreatment, and poor mother-child relations also predicted early alcohol use. Conclusions: Maltreated children are at high risk for psychiatric, alcohol, and substance abuse problems. Examination of genetic and environmental risk and protective factors can help identify those who are most vulnerable and help guide prevention and intervention efforts.

Kendler KS; Kuo PH; Webb BT; Kalsi G; Neale MC; Sullivan PF et al. A joint genomewide linkage analysis of symptoms of alcohol dependence and conduct disorder. Alcoholism: Clinical and Experimental Research 30(12): 1972-1977, 2006. (19 refs.)

Background: A large linkage peak for alcohol dependence (AD) was detected on chromosome 4q in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD). Are the susceptibility genes underlying this peak specific for AD or do they increase risk for externalizing disorders more generally? Can we, in the IASPSAD, replicate prior evidence for linkage to conduct disorder (CD)? Methods: The 733 all possible sibling pairs in IASPSAD were typed for 1,020 short-tandem-repeat genetic markers. Univariate and bivariate linkage analyses were conducted by the program sequential oligogenic linkage analysis routines (SOLAR), for both the raw and the transformed number of symptoms of AD (ADsx) and number of symptoms of CD (CDsx). In the bivariate analyses, specificity was assessed by the ratio of the variance accounted for in ADsx and CDsx by the quantitative trait locus. Results: In the univariate linkage analyses, no evidence for linkage to CDsx was found under the 4q peak for ADsx and the largest peaks for CDsx were seen on chromosomes 1q (LOD=3.16) and 14p (LOD=2.36). In the bivariate linkage analysis, the 4q peak had high specificity for AD (AD/CD ratio of 39.9). Several smaller peaks, on chromosomes 1, 7, and 10, had moderate specificity for CD but also impacted on risk for AD, with AD/CD ratios of 0.18 to 0.32. Conclusions: Genes under the 4q linkage peak for AD in the IASPSAD impact specifically on risk for AD rather than more broadly on risk for externalizing syndromes. Suggestive linkages were found in several locations for CD, 2 of which broadly replicate prior findings. The bivariate analyses identified genomic locations containing susceptibility loci that impacted on risk for both CDsx and ADsx.

Kim J-W; Park CS; Hwang J-W; Shin M-S; Hong K-E; Cho S-C et al. Clinical and genetic characteristics of Korean male alcoholics with and without attention deficit hyperactivity disorder. Alcohol and Alcoholism 41(4): 407-411, 2006. (49 refs.)

Aims: To examine the clinical and genetic characteristics of Korean male alcoholics with and without attention deficit hyperactivity disorder (ADHD). Methods: The present study included 85 male alcoholics who were diagnosed as having DSM-IV alcohol dependence. A total of 28 (32.9%) alcoholics were diagnosed as having DSM-IV ADHD with ongoing symptoms in adulthood. For the evaluation of their psychiatric conditions, the alcohol dependence scale (ADS), Beck depression inventory (BDI), Beck anxiety inventory (BAI), Barratt impulsiveness scale (BIS), brief anger-aggression questionnaire (BAQ), overt aggression scale (OAS), codependence test, and obsessive compulsive drinking scale (OCDS) were administered. The genotype frequencies of the dopamine type 2 receptor gene (DRD2), aldehyde dehydrogenase type 2 gene (ALDH2), functional polymorphism in the regulatory region of the serotonin transporter gene (5-HTTLPR), and catechol-O-methyltransferase gene (COMT) polymorphisms were examined. Results: Compared with alcoholics without ADHD, the mean ages for the onset of pathological drinking and alcohol withdrawal hallucinations were significantly earlier in alcoholics with ADHD. There was also a significant difference in the history of antisocial behaviour between the two groups. Compared with alcoholics without ADHD, the mean scores of the ADS, BDI, BAI, OAS, and OCDS were significantly higher in alcoholics with ADHD. With regard to the codependence test results, the mean scores of the interpersonal problem, low self-esteem and anxiety/fear subscales, and the mean total score of the codependence test were significantly higher in alcoholics with ADHD when compared with those without ADHD. There were no significant differences in the genotype frequencies of the DRD2, ALDH2, 5-HTTLPR, and COMT polymorphisms between alcoholics with and without ADHD. Conclusions: The results of this study suggest that the comorbidity of alcohol dependence and ADHD in this Korean sample forms a distinct clinical phenotype that shows an increased severity of alcohol-related symptoms and behavioural/emotional problems and that ADHD is associated with an increased risk for the early onset of alcohol dependence in Korean male alcoholics.

Klein TA; Neumann J; Reuter M; Hennig J; von Cramon DY; Ullsperger M. Genetically determined differences in learning from errors. Science 318(5856): 1642-1645, 2007. (28 refs.)

The role of dopamine in monitoring negative action outcomes and feedback-based learning was tested in a neuroimaging study in humans grouped according to the dopamine D2 receptor gene polymorphism DRD2-TAQ-IA. In a probabilistic learning task, A1-allele carriers with reduced dopamine D2 receptor densities learned to avoid actions with negative consequences less efficiently. Their posterior medial frontal cortex (pMFC), involved in feedback monitoring, responded less to negative feedback than others' did. Dynamically changing interactions between pMFC and hippocampus found to underlie feedback-based learning were reduced in A1-allele carriers. This demonstrates that learning from errors requires dopaminergic signaling. Dopamine D2 receptor reduction seems to decrease sensitivity to negative action consequences, which may explain an increased risk of developing addictive behaviors in A1-allele carriers.

Knopik VS; Heath AC; Jacob T; Slutske WS; Bucholz KK; Madden PAF et al. Maternal alcohol use disorder and offspring ADHD: Disentangling genetic and environmental effects using a children-of-twins design. Psychological Medicine 36(10): 1461-1471, 2006. (56 refs.)

Background. Children of alcoholics are significantly more likely to experience high-risk environmental exposures, including prenatal substance exposure, and are more likely to exhibit externalizing problems [e.g. attention deficit hyperactivity disorder (ADHD)]. While there is evidence that genetic influences and prenatal nicotine and/or alcohol exposure play separate roles in determining risk of ADHD, little has been done on determining the joint roles that genetic risk associated with maternal alcohol use disorder (AUD) and prenatal risk factors play in determining risk of ADHD. Method. Using a children-of-twins design, diagnostic telephone interview data from high-risk families (female monozygotic and dizygotic twins concordant or discordant for AUD as parents) and control families targeted from a large Australian twin cohort were analyzed using logistic regression models. Results. Offspring of twins with a history of AUD, as well as offspring of non-AUD monozygotic twins whose co-twin had AUD, were significantly more likely to exhibit ADHD than offspring of controls. This pattern is consistent with a genetic explanation for the association between maternal AUD and increased offspring risk of ADHD. Adjustment for prenatal smoking, which remained significantly predictive, did not remove the significant genetic association between maternal AUD and offspring ADHD. Conclusions. While maternal smoking during pregnancy probably contributes to the association between maternal AUD and offspring ADHD risk, the evidence for a significant genetic correlation suggests: (i) pleiotropic genetic effects, with some genes that influence risk of AUD also influencing vulnerability to ADHD; or (ii) ADHD is a direct risk-factor for AUD.

Koehnke MD. Approach to the genetics of alcoholism: A review based on pathophysiology. (review). Biochemical Pharmacology 75(1): 160-177, 2008. (238 refs.)

Alcohol dependence is a common disorder with a heterogenous etiology. The results of family, twin and adoption studies on alcoholism are reviewed. These studies have revealed a heritability of alcoholism of over 50%. After evaluating the results, it was epidemiologically stated that alcoholism is heterogenous complex disorder with a multiple genetic background. Modern molecular genetic techniques allow examining specific genes involved in the pathophysiology of complex diseases such as alcoholism. Strategies for gene identification are introduced to the reader, including family-based and association studies. The susceptibility genes that are in the focus of this article have been chosen because they are known to encode for underlying mechanisms that are linked to the pathophysiology of alcoholism or that are important for the pharmacotherapeutic approaches in the treatment of alcohol dependence. Postulated candidate genes of the metabolism of alcohol and of the involved neurotransmitter systems are introduced. Genetic studies on alcoholism examining the metabolism of alcohol and the dopaminergic, GABAergic, glutamatergic, opioid, cholinergic and serotonergic neurotransmitter systems as well as the neuropeptide Y are presented. The results are critically discussed followed by a discussion of possible consequences.

Kohnke MD; Kolb W; Lutz U; Maurer S; Batra A. The serotonin transporter promotor polymorphism 5-HTTLPR is not associated with alcoholism or severe forms of alcohol withdrawal in a German sample. (letter). Psychiatric Genetics 16(6): 227-228, 2006. (4 refs.)

Koob GF. Alcoholism, corticotropin-releasing factor, and molecular genetic allostasis. (editorial). Biological Psychiatry 63(2): 137-138, 2008. (10 refs.)

Kuo PH; Neale MC; Riley BP; Patterson DG; Walsh D; Prescott CA et al. A genome-wide linkage analysis for the personality trait neuroticism in the Irish affected sib-pair study of alcohol dependence. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 144B(4): 463-468, 2007. (38 refs.)

Neuroticism is a personality trait which reflects individual differences in emotional stability and vulnerability to stress and anxiety. Consistent evidence shows substantial genetic influences on variation in this trait. The present study seeks to identify regions containing susceptibility loci for neuroticism using a selected sib-pair sample from Ireland. Using Merlin regress, we conducted a 4 cM whole-genome linkage analysis on 714 sib-pairs. Evidence for linkage to neuroticism was found on chromosomes 11p, 12% and 15q. The highest linkage peak was on 12q at marker D12S1638 with a Lod score of 2.13 (-log p = 2.76, empirical P-value < 0.001). Our data also support gender specific loci for neuroticism, with male specific linkage regions on chromosomes 1, 4, 11, 12, 15, 16, and 22, and female specific linkage regions on chromosomes 2,4,9,12,13, and 18. Some genome regions reported in the present study replicate findings from previous linkage studies of neuroticism. These results, together with prior studies, indicate several potential regions for quantitative trait loci for neuroticism that warrant further study.

Larkins JM; Sher KJ. Family history of alcoholism and the stability of personality in young adulthood. Psychology of Addictive Behaviors 20(4): 471-477, 2006. (48 refs.)

The authors examined the magnitude and durability of personality differences related to family history of alcoholism (FH) and the development of alcohol use disorders (AUDs) in late adolescence and early adulthood. Data were taken from a longitudinal sample (N = 487; approximately half FH-positive [+]) who completed the Eysenck Personality Questionnaire (H. J. Eysenck & S. B. G. Eysenck, 1975) at 3 points spanning 11 years (participants were 18 years old at baseline). Hierarchical linear analyses showed that FH+ participants had higher levels of neuroticism and psychoticism over the study period, independent of AUD. Despite relatively large mean decreases in neuroticism (as well as extraversion), the magnitude of the between-groups differences found at age 18 were maintained over the next decade. These changes thus reflect stable underlying differences in personality and not artifacts of higher rates of AUDs in FH+ individuals, recently living in an alcoholic home, vulnerability to the developmental challenge of leaving home, and/or a developmental lag.

Laucht M; Becker K; Blomeyer D; Schmidt MH. Novelty seeking involved in mediating the association between the dopamine D4 receptor gene Exon III polymorphism and heavy drinking in male adolescents: Results from a high-risk community sample. Biological Psychiatry 61(1): 87-92, 2007. (49 refs.)

Background: Previous research suggests that personality traits, particularly novelty seeking (NS), increase the risk of substance abuse. One possible explanation to account for this association relates to common genetic factors. The aim of this study was to examine whether allelic variants of the dopamine D4 receptor gene (DRD4) are associated with alcohol use in adolescents and to determine the extent to which these links are mediated by NS.MethodsThree hundred three adolescents (144 male participants, 159 female participants, approximately 15 years old) from a high-risk community sample completed self-report questionnaires measuring alcohol intake and temperament (Junior Temperament and Character Inventory [JTCI]). DNA was genotyped for the DRD4 exon III polymorphism. Results: Male participants carrying the 7-repeat allele of DRD4 drank higher maximum amounts of alcohol per occasion and had greater lifetime rates of heavy drinking than male participants without this allele. Higher levels of NS were associated with higher alcohol intake in both genders. Multiple regression analyses support the role of NS in mediating the relationship between DRD4 and heavy drinking in male adolescents but not in female adolescents. Conclusions: These findings extend previous work highlighting the significance of personality traits as a mediating factor between genetic susceptibility and substance use during the period of early experimental use.

Le Strat Y; Ramoz N; Pickering P; Burger V; Boni C; Aubin HJ. The 3' part of the dopamine transporter gene DAT1/SLC6A3 is associated with withdrawal seizures in patients with alcohol dependence. Alcoholism: Clinical and Experimental Research 32(1): 27-35, 2008. (69 refs.)

Background: Some studies have reported that the A9 allele of the variable nucleotide tandem repeat (VNTR) of the gene which encodes the dopamine transporter (DAT1/SLC6A3) is associated with alcoholism withdrawal symptoms such as alcohol withdrawal seizures (WSs), whereas others did not. We investigated whether polymorphisms within the DAT1 gene are associated with WS taking into account some of the confounding factors such as the severity of alcohol dependence. Methods: To further assess the role of this gene in WS, we genotyped the VNTR and 7 single nucleotide polymorphisms (SNPs) encompassing the DAT1 gene in a sample of 250 alcohol-dependent subjects (175 men and 75 women), of whom 24% exhibited WSs, taking into account the severity of alcohol dependence. Results: The VNTR is associated with an increased risk of WSs (odd ratio = 3.5; p = 0.019), even when controlling for confounding factors (p = 0.031). As 2 SNPs, in roughly the same location of the gene (namely rs27072 and rs27048), are also associated with WSs, it is possible that the initial association of the VNTR polymorphism was tagging a specific haplotype of this gene. Indeed, in our sample of alcohol-dependent patients, 2 haplotypes were associated with a significantly different risk of WSs. Conclusions: The present study adds evidence for a significant role of the 3' part of the DAT1 gene in WS of alcohol-dependent patients, not only because it is in accordance with previous work, but also because of larger statistical power (as relying on a sample over sampled with the studied phenotype), as it gives a more precise analysis of different SNPs within the DAT1 gene, and as it confirms the association when major potentially confounding factors are taken into account in a logistical regression analysis.

Li TK; Volkow ND; Baler RD; Egli M. The biological bases of nicotine and alcohol co-addiction. Biological Psychiatry 61(1): 1-3, 2007. (37 refs.)

Alcohol and nicotine kill over half a million Americans every year. Abuse and addiction to these drugs represent the leading cause of preventable morbidity and mortality in the United States. Almost 50 million Americans smoke cigarettes, and close to 20 million either abuse or are addicted to alcohol. Equally important to remember, albeit beyond the scope of this commentary, is the fact that these addictions display a strong comorbidity with a host of psychiatric conditions. Given these prevalence figures and the economic burden associated with them, it is critical to investigate the underlying causes of these addictions, with particular regard -- as emphasized in this special issue of Biological Psychiatry -- to their interactions that, if not recognized, might hinder effective treatment and prevention efforts. A thorough understanding of such mechanisms will allow the development of evidence-based interventions that could greatly impact public health. There is discussion of a sharing of genes, a sharing of circuits, and the sharing of behaviors and treatment.

Loza AJM; Iglesias MTR; Diaz IP; Castellanos SC; Andrade CG; Mora MEM et al. Association of alcohol-metabolizing genes with alcoholism in a Mexican Indian (Otomi) population. Alcohol 39(2): 73-79, 2006. (56 refs.)

Association studies provide a powerful approach to link DNA variants and genetic predisposition to complex diseases. In this study, we determined the genotype and allelic frequencies of genes encoding enzymes involved in alcohol metabolism in alcoholic and nonalcoholic subjects of related ethnicity. A total of 118 individuals of Otomi Mexican Indian ancestry were included. Fifty-nine were chronic alcoholics according to WHO criteria and alcohol dependents according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM IV) criteria. They were compared to 59 teetotalers or alcohol consumers of < 10 g per day. The restriction fragment length polymorphisms analyzed were ADH1B/MaeIII, ALDH2/MboII, CYP2E1/DraI, CYP2E1/RsaI, and CYP2E1/TaqI. Of the studied polymorphisms, a significant difference between alcoholic and nonalcoholic Otomies was observed only in the CYP2E1/TaqI. The common genotype in alcoholics was A1/A2 (54%), and in nonalcoholics the homozygous A2/A2 (63%) (odds ratio [OR]: 0.28; 95% confidence interval [CI]: 0.13-0.60; P = .002). The frequency of the mutant allele A1 was significantly higher in alcoholics than in nonalcoholics (41 vs. 21%; OR: 2.4; 95% CI: 1.3-4.3; P = .003). This documents the presence of a polymorphism of CYP2E1 that is overexpressed in alcoholic Otomies, in which the variant allele (A1 of CYP2E1/TaqI) is associated with increased susceptibility to alcoholism. The appreciation that this finding may be an additional factor contributing to the high frequency of liver cirrhosis in Otomies requires further investigation.

Luo XG; Kranzler HR; Zuo LJ; Wang S; Schork NJ; Gelernter J. Multiple ADH genes modulate risk for drug dependence in both African- and European-Americans. Human Molecular Genetics 16(4): 380-390, 2007. (54 refs.)

Drug dependence (DD) is commonly co-morbid with alcohol dependence (AD). Many studies have also shown common genetic risk factors for these disorders. We previously reported associations of AD with seven alcohol dehydrogenase (ADH) genes. The present study examines the relationship between these genes and DD. We genotyped 16 markers within the ADH gene cluster and 38 unlinked ancestry-informative markers in a case-control sample of 718 individuals. All markers were consistent with Hardy-Weinberg equilibrium in controls, but some markers showed Hardy-Weinberg disequilibrium in cases (minimal P = 0.002). Genotypes of many markers were associated with DD, both before and after controlling for admixture effects (minimal P < 1.0 x 10(-6)). Diplotype trend regression analysis showed that ADH5 and ADH6 genotypes, and diplotypes at ADH1A, ADH1B, ADH1C and ADH7 (minimal P = 0.002), were associated with DD in European-Americans and/or African-Americans. This first report of an allelic association of these loci with DD provides new insight into the mechanism of genetic risk for DD. These findings, obtained using a series of powerful and reliable analytic methods, may also help to explain the high rate of co-morbidity between AD and DD.

Lyons MJ; Schultz M; Neale M; Brady K; Eisen S; Toomey R et al. Specificity of familial vulnerability for alcoholism versus major depression in men. Journal of Nervous and Mental Disease 194(11): 809-817, 2006. (24 refs.)

There are various hypotheses regarding comorbidity between alcohol dependence (AD) and major depression (MD). We interviewed 3372 pairs of male twins assessing DSM-III-R MD and AD. Individuals with comorbid MD and AD exhibited greater severity of each disorder than individuals with only one. MD in one twin was associated with risk of MD alone and MD plus AD, but not AD alone in the cotwin. AD in one twin was associated with risk of AD alone and AD plus MD, but not MD alone in the cotwin. The best fitting biometrical comorbidity model was the reciprocal causation model in which AD can cause MD and vice versa. However, a model in which genetic and environmental influences on each disorder were correlated could not be definitively rejected. Our data are most consistent with a mechanism of reciprocal causation, whereby MD increases risk for AD and AD increases risk of MD.

MacKillop J; Menges DP; McGeary JE; Lisman SA. Effects of craving and DRD4 VNTR genotype on the relative value of alcohol: an initial human laboratory study. Behavioral and Brain Functions 3: article 11, 2007. (85 refs.)

Background: Craving for alcohol is a highly controversial subjective construct and may be clarified by Loewenstein's visceral theory, which emphasizes craving's behavioral effects on the relative value of alcohol. Based on the visceral theory, this study examined the effects of a craving induction on the relative value of alcohol as measured by a behavioral choice task. In addition, based on previous evidence of its role in the expression of craving, the influence of DRD4 VNTR genotype (DRD4-L vs. DRD4-S) was also examined. Methods: Thirty-five heavy drinkers (54% male; 31% DRD4-L) were randomly assigned to receive either a craving induction (exposure to personally relevant alcohol cues) or a control induction (exposure to neutral cues), which was followed by an alcohol-money choice task. Participants were assessed for craving and positive/negative affect throughout the procedure, and relative value of alcohol was derived from participant choices for alcohol versus money. DRD4 VNTR status was assessed retrospectively via buccal samples using previously established protocols. Results: Factorial analysis of the craving induction revealed that it was associated with significant increase in craving (p <.001), but not greater relative value of alcohol. Factorial analyses including DRD4 VNTR genotype of did not suggest an influence on reactivity to the craving induction, although this analysis was substantially compromised by small cell sample sizes. Continuous analyses revealed that craving was significantly associated with the relative value of alcohol (p <.05) and possession of the DRD4-L allele further amplified this relationship (p <.001). Conclusion: These results are interpreted as generally supporting Loewenstein's visceral theory of craving and evidence of a functional role of DRD4 VNTR genotype in the expression of craving for alcohol. Methodological limitations, mechanisms underlying these findings, and future directions are discussed.

Matsuo K; Hiraki A; Hirose K; Ito H; Suzuki T; Wakai K et al. Impact of the alcohol-dehydrogenase (ADH) 1C and ADH1B polymorphisms on drinking behavior in nonalcoholic Japanese. Human Mutation 28(5): 506-510, 2007. (33 refs.)

A linkage disequilibrium (LD) between the alcohol-dehydrogenase 1B (ADH1B) and alcohol-dehydrogenase 1C (ADH1C) polymorphisms adds complexity to differentiating the significance of these two genetic polymorphisms on drinking behavior and alcoholism. We have recently shown the importance of the ADH1B polymorphism on habitual drinking in the Japanese population; however, the issue regarding the LD between the ADH1B and ADH1C polymorphisms remains to be clarified. Here, we conducted a cross-sectional study in 2,299 nonalcoholic Japanese individuals. Drinking behavior was examined with regard to haplotypes of the ADH1B and ADH1C polymorphisms. Strength of association was assessed by sex and alaehyde-dehydrogenase 2 (ALDH2) adjusted odds ratios (OR) and their 95% confidence intervals (CIs) for the haplotype of the ADH1B and ADH1C polymorphisms. The ORs for habitual drinking were significant for ADH1B*2(rapid), ADHIC*2(slow) (OR = 1.03; 95% CI: 1.01-1.05), ADHIB*1 (slow)-ADH1C*1 (rapid) (OR = 1.15; 95% CI: 1.14-1.16), and ADH1B*1 (slow)-ADH1C*2 (slow) (OR= 1.31; 95% CI: 1.29-1.32) compared with ADH1B*2 (rapid) ADH1C*1 (rapid). This trend was evident among mates. Similarly, a significantly increased risk of heavy drinking was observed for each haplotype compared with ADH1B*2 (rapid)-ADH1C*1 (rapid). In conclusion, this study showed a significant impact of the ADH1C polymorphism on habitual drinking, regardless of the ADH1B/ALDH2 polymorphisms.

Miles MF; Williams RW. Meta-analysis for microarray studies of the genetics of complex traits. Trends in Biotechnonology 25(2): 45-47, 2007. (10 refs.)

In comparison to other complex disease traits, alcoholism and alcohol abuse are influenced by the combined effects of many genes that alter susceptibility, phenotypic expression and associated morbidity, respectively. Many genetic studies, in both animal models and humans, have identified genetic intervals containing genes that influence alcoholism or behavioral responses to ethanol. Concurrently, a growing number of microarray studies have identified gene expression differences related to ethanol drinking or other ethanol behaviors. However, concerns about the statistical power of these experiments, combined with the complexity of the underlying phenotypes, have greatly hampered the identification of candidate genes underlying ethanol behaviors. Meta-analysis approaches using recent compilations of large datasets of microarray, behavioral and genetic data promise improved statistical power for detecting the genes or gene networks affecting ethanol behaviors and other complex traits.

Montane-Jaime K; Moore S; Shafe S; Joseph R; CrookSa H; Carr L et al. ADH1C2 allele is associated with alcohol dependence and elevated liver enzymes in Trinidad and Tobago. Alcohol* 39(2): 81-86, 2006. (34 refs.)

Variants in alcohol dehydrogenase (ADH) genes differ between ethnic groups and have, in some studies, been found to be associated with alcohol dependence and alcoholic liver disease. This study sought to determine whether an association exists between ADH (ADH1C previously ADH3, ADH1B*2 previously ADH2*2) genotypes, alcohol dependence, drinking history, and liver function tests in the two major ethnic groups of Trinidad and Tobago (TT). One hundred and forty-five alcohol-dependent individuals of both East Indian (Indo-TT) and African (Afro-TT) ancestry, and 108 controls matched by age, sex, and education participated in the study. Serum levels of alanine and aspartate aminotransferase (ALT, AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and gamma-glutamyltransferase (GGT) as well as presence of HIV, hepatitis B surface antigen, and anti-hepatitis C virus antibody were determined. There was a significant difference in the distribution of ADH1C allele polymorphisms between the ethnic groups (P < .0001). Forty-three percent of the Indo-TT were found to have one ADH1C*2 allele and 5% were homozygous, whereas, only 23% of Afro-TT had one allele and one was homozygous. Only three individuals had an ADH1B*2 allele (one Indo-TT alcohol dependent, two Indo-TT controls). The ADH1C*2 allele was significantly associated with alcohol dependence overall and within Indo-TT ancestry, however, it was not associated with current or heaviest alcohol consumption levels. Individuals with at least one ADH1C*2 allele also had significantly elevated levels of ALP (P < .02) and GGT (P < .02) as compared to individuals homozygous for ADH1C*. Additionally, GGT levels were also found to be elevated (P < .02) within Indo-TT alcohol dependents with at least one ADH1C*2 allele but not within the Afro-TT alcohol dependents with that allele. A linear regression that included alcohol dependence and levels of alcohol consumption confirmed that levels of serum GGT were significantly associated with the ADH1C*2 genotype. These results suggest that ADH1C polymorphisms are associated with alcohol dependence and alcohol associated elevations of liver enzymes in a population with a low frequency of ADH1B2 alleles.

Munafo MR; Matheson IJ; Flint J. Association of the DRD2 gene Taq1A polymorphism and alcoholism: A meta-analysis of case-control studies and evidence of publication bias. Molecular Psychiatry 12(5): 454-461, 2007. (61 refs.)

We investigated the association of the dopamine D2 receptor ( DRD2) Taq1A polymorphism and alcoholism, using meta-analytic techniques, and specifically undertook an investigation of possible publication bias. Potential publication bias represents a genuine risk to the integrity of published research, but its impact has rarely been documented. We observed a small effect of the DRD2 Taq1A polymorphism on risk of alcoholism, indicating increased alcoholism in individuals possessing the A1 allele of the Taq1A polymorphism (OR = 1.21, 95% CI 1.13 - 1.30, P < 0.001). This association remained significant when data from samples of European and East Asian ancestry were analyzed separately. We did not find evidence for association in high- severity alcoholism compared to low- severity alcoholism. Removing the first published study significantly reduced the magnitude of the pooled effect size estimate, although the association remained significant. In addition, we observed evidence for possible publication bias and for the strength of individual study effect size to be inversely related to year of publication. These results support the association of the DRD2 Taq1A polymorphism with alcoholism. This conclusion is qualified by the possibility of publication bias in the literature and the observed between- study heterogeneity, which indicates that the observed association may differ in strength between populations or may not exist at all in some populations.

Neumark YD; Lopez-Quintero C; Grinshpoon A; Levinson D. Alcohol drinking patterns and prevalence of alcohol-abuse and dependence in the Israel national health survey. Israel Journal of Psychiatry and Related Sciences 44(2): 126-135, 2007. (47 refs.)

Background: Coexistence of disparate religious/cultural mores with regard to alcohol drinking within the changing social milieu of Israel provides an informative environment for investigation of alcohol consumption patterns and alcohol-related mental disorders. Method: A national population-based survey of Israeli adults was conducted as part of the WHO/World Mental Health Survey initiative. Logistic regression models accommodated the complex sampling design and accounted for potential confounders. Results: Half of the 4,859 respondents reported any alcohol consumption in the year prior to interview; 5% drink 3 or more times weekly. DSM-IV criteria for alcohol-abuse or dependence (lifetime) were met by 4.3% of respondents. Significantly higher rates were found among males (AOR, adjusted odds ratio=7.3), younger adults (AOR=5.0), immigrants from the former Soviet Union (AOR=2.0), and those who were never married (AOR=1.6). Limitations: Under-reporting remains a potential concern in health behavior surveys, particularly in the face of opposing religious norms. Conclusions: The lifetime prevalence of alcohol abuse in Israel is identical to other European countries while drinking levels are considerably lower, suggesting a biological sensitivity alongside socio-cultural factors.

Nurnberger JI; Bierut LJ. Seeking the connections: Alcoholism and our genes. Scientific American 296(4): 46-53, 2007. (3 refs.)

The tendency to become dependent on alcohol has long been known to run in families, which for some only added to the social stigma attached to this complicated condition. But to scientists, that apparent heritability suggested that some genetic component underlying vulnerability to alcohol problems was being transmitted from generation to generation.

Ocaranza P; Quintanilla ME; Tampier L; Karahanian E; Sapag A; Israel Y. Gene therapy reduces ethanol intake in an animal model of alcohol dependence. Alcoholism: Clinical and Experimental Research 32(1): 52-57, 2008. (42 refs.)

Background: Some gene polymorphisms strongly protect against the development of alcoholism. A large proportion of East Asians carry a protective inactivating mutation in aldehyde dehydrogenase (ALDH2*2). These subjects display high levels of blood acetaldehyde when consuming alcohol, a condition that exerts a 66 to 99% protection against alcohol abuse and alcoholism. Present knowledge allows the incorporation of therapeutic genes that can modify the expression of disease predisposing genes, an effect that can last from months to years. In line with the above, we have tested if inhibiting the expression of the aldehyde dehydrogenase gene (ALDH2) by an anti-Aldh2 antisense gene can curtail the drive of alcohol-dependent animals to consume alcohol. Methods: Wistar-derived rats bred as high alcohol drinkers (UChB; Universidad de Chile Bibulous) were rendered alcohol dependent by a 2-month period of voluntary ethanol (10%) intake, subjected to a 3-day withdrawal period and further allowed access to 10% ethanol for only 1 hour each day. This condition results in a high ethanol intake (1.2 g/kg/60 min) which is 10 times higher than that of naive UChB rats. Results: The single intravenous administration of an anti-Aldh2 antisense gene carried by an adenoviral vector reduced liver ALDH2 activity by 85% (p < 0.002) and inhibited voluntary ethanol intake by 50% (ANOVA p < 0.005) for 34 days. Conclusions: This proof-of-principle study indicates that gene therapy approaches can be employed to achieve a long-term reduction of alcohol intake in alcohol-dependent animals and suggests that gene vectors may be developed as long-lasting therapeutic adjuncts for the treatment of alcoholism.

Rangaswamy M; Jones KA; Porjesz B; Chorlian DB; Padmanabhapillai A; Kamarajan C et al. Delta and theta oscillations as risk markers in adolescent offspring of alcoholics. (review). International Journal of Psychophysiology 63(1): 3-15, 2007. (118 refs.)

Background: Visual P300 is consistently lower in alcohol-dependent individuals, their offspring and subjects at risk. Delta and theta event-related oscillations (ERO) are the major contributors to the P300 signal. The total and evoked power in delta and theta bands in the 300 to 700 ins post-stimulus window (corresponding to the zone of P300 maxima) was compared between adolescent offspring of alcoholics (high-risk) and age-matched normal controls (low-risk), to assess the utility of the risk markers. Methods: EEG was recorded during the performance of a visual oddball task. The S-transform algorithm decomposed the EEG signals into different frequency bands and the group differences in total and evoked power in the oscillatory responses during the P300 time window (300 to 700 ins) were analyzed using a multivariate design. Similar analysis was performed on P300 peak amplitude for the target. Results: The high-risk group showed significantly lower parietal post-stimulus evoked and total power in the delta band for targets. A decrease in total power was seen centrally and parietally in the theta band. The P300 peak amplitude in the parietal electrodes was also significantly lower in the high-risk group. Conclusions: The decreased total theta power and total and evoked delta power for visual targets in high risk individuals may serve as an endophenotypic marker in the development of alcoholism and other disinhibitory disorders. The differences seen between the offspring of alcoholics and controls may have a cholinergic basis. The ERO measures appear to be more robust than the P300 amplitude in differentiating the groups.

Rasmussen F; Kark M; Tholin S; Karnehed N; Tynelius P. The Swedish Young Male Twins Study: A resource for longitudinal research on risk factors for obesity and cardiovascular diseases. Twin Research and Human Genetics 9(6): 883-889, 2006. (16 refs.)

The Swedish Young Male Twins Study is a population-based longitudinal twin study founded in 1997 through record-linkages of several national registers. Details on pregnancy and birth were obtained from the Swedish Medical Birth Register and used to identify 3566 male twins (1783 pairs) born in Sweden between 1973 and 1979 and resident in Sweden in 1997. A record-linkage was made between the Medical Birth Register and the Military Service Conscription Register for the years 1991 to 1999, providing information on body weight, height, blood pressure, muscle strength, cognitive ability of these twins at age 18 and 19 years. In 1998, 2002 and 2005 to 2006, the twins were surveyed on their zygosity, socioeconomic status, lifestyle factors (such as eating habits, physical activity, smoking habits, use of alcohol etc), height and weight. In 2002, additional information was collected on perceived body shape and size, and eating behavior, according to the Three-Factor Eating Questionnaire. In 2003, DNA via buccal mucosa was collected from a subset of the twins. Recent research using the Swedish Young Male Twins datasets has explored the relationships between fetal growth, body size and blood pressure in young adulthood, genetic and environmental contributions to eating behavior and physical activity, and relationships between diet and physical activity patterns with longitudinal changes in body mass index and attained waist circumference.

Reuter M; Jeste N; Klein T; Hennig J; Goldman D; Enoch MA et al. Association of THR105Ile, a functional polymorphism of histamine N-methyltransferase (HNMT), with alcoholism in German Caucasians. Drug and Alcohol Dependence 87(1): 69-75, 2007. (36 refs.)

Background: CNS histamine has been shown to have an inhibitory effect on reward and it is implicated in the etiology of addiction and stress. Histamine N-methyltransferase (HNMT) is believed to be the sole pathway for termination of the neurotransmitter action of histamine in mammalian brain. A common, functional polymorphism, a C314T transition in the HNMT gene, results in a Thr105Ile substitution of the protein encoded. A recent study has shown that the frequency of the Ile105 allele was significantly lower in alcoholics compared to that in non-alcoholics in Finns and Plains American Indians. Following up these results, we tested whether the Thr105Ile polymorphism was associated with alcoholism in German Caucasians. Methods: Thr105Ile was genotyped in n=366 psychiatrically interviewed German Caucasian ICD-10 lifetime alcoholics, along with n=200 ethnically matched controls. Results: No significant difference was found in the frequency of the Ile105 allele between alcoholics (0.11) and controls (0.10) (chi(2) = 0.21, d.f. = 1, p = 0.647). Likewise, genotype distributions did not differ significantly. However, the frequency of the Ile105 allele was significantly lower in male alcoholics with a family history of alcoholism compared to that in male alcoholics without a family history of alcoholism (chi(2) = 4.07, d.f. = 1, p = 0.044). Conclusions: In German Caucasians the association of the HNMT Thr105Ile polymorphism with alcoholism was not replicated per se, but a congruent association was found between the Ile105 allele and family history of alcoholism supporting the protective role of the Ile105 allele against alcoholism.

Rhea SA; Gross AA; Haberstick BC; Corley RP. Colorado Twin Registry. Twin Research and Human Genetics 9(6): 941-949, 2006. (26 refs.)

The Colorado Twin Registry (CTR) is a population-based registry housed at the Institute for Behavioral Genetics, University of Colorado. Recruited subjects' birth years date from 1968. Four samples comprise the CTR: the Community Twin Sample, Infant Twin Sample, Longitudinal Twin Sample, and the Early Reading Development Sample. Criteria for enrollment, recruitment strategies, demographic information and zygosity assignment are explained for each sample. In addition, 8 studies in which CTR twins have participated are highlighted. These include studies of early cognition, early reading ability, executive cognitive function, and vulnerability to substance abuse and antisocial behavior. Goals, measures, and brief results are provided for each study. The development of the CTR is an ongoing and evolving process, and it has proved to be a valuable resource, relatively representative of the population from which it was drawn.

Rohsenow DJ; Miranda R; McGeary JE; Monti PM. Family history and antisocial traits moderate naltrexone's effects on heavy drinking in alcoholics. Experimental and Clinical Psychopharmacology 15(3): 272-281, 2007. (54 refs.)

Naltrexone's (NAL) effects on alcohol consumption are generally modest, so identifying patients likely to benefit would improve treatment utility. Several studies indicate that potentially significant moderators of naltrexone's effects might include family history of alcohol problems (FH), age of onset of alcohol problems, degree of antisocial traits, and comorbid drug use. Data from 128 alcoholic patients enrolled in a 12-week naltrexone treatment study (50 mg/day) were reanalyzed to determine the role of FH, age of onset, antisocial traits, and comorbid drug use in naltrexone's treatment effects on heavy drinking days. Dichotomized FH, age of onset of alcohol problems, and comorbid cocaine or marijuana use had no interaction effect with medication. Percentage of relatives with problem drinking (family history percentage [FHP]) moderated the effects of naltrexone on drinking such that naltrexone resulted in lower drinking rates only for patients with higher FHP. Antisocial traits also moderated the effects of medication on drinking for patients compliant with >= 70% of medication. Patients with more antisocial traits had less heavy drinking on naltrexone than on placebo, whereas patients low on antisocial traits had no benefit from naltrexone. Covarying antisociality in regressions of drinking outcome on FHP showed that the effects of FHP were not attributable to antisociality. Thus, naltrexone may selectively benefit alcoholics with antisocial traits or 20% or more relatives with problem drinking.

Sakai JT; Hopfer CJ; Hartman C; Haberstick BC; Smolen A; Corley RP et al. Test of association between TaqIA A1 allele and alcohol use disorder phenotypes in a sample of adolescent patients with serious substance and behavioral problems. Drug and Alcohol Dependence 88(2/3): 130-137, 2007. (59 refs.)

Several studies have demonstrated a significant association between the A1 allele of the TaqIA polymorphism, and various phenotypes of alcoholism, others have not, and two studies have shown the reversed association, where the A2 allele was associated with higher levels of alcohol consumption. We sought to test for an association between early onset (in childhood or adolescence) alcohol use disorders and the DRD2 TaqIA polymorphism and to resolve some of the hypothesized explanations for previous negative results, utilizing a larger sample than many previous studies. Methods: We selected individuals with a lifetime alcohol abuse or dependence (n = 239) diagnosis from a clinically ascertained sample of youth (ages 13-19) with serious conduct and substance problems (about 90% also met criteria for conduct disorder and a cannabis use disorder) and compared them with individuals without a lifetime alcohol us(e) disorder diagnosis ascertained from (1) community adolescent controls (n = 151), (2) siblings of patients (n = 87) and (3) other adolescent patients (n = 92). Cases were compared with each control group, separately, by genotype using the chi(2)-test. Using 78 adolescent patients with an alcohol use disorder where genotypic information was available for both parents, we conducted the transmission disequilibrium test (TDT). Results: Case-control results were non-significant using the entire community control sample (chi(2)(2) =1.92; p = 0.38) and when restricting the sample to Caucasians (chi(2)(2) = 3.81; p = 0.15) or Hispanics (chi(2)(2) = 1.70; p = 0.43). Case-control results using the other comparison groups and TDT results were also non-significant. Discussion: We did not find support for an association between the TaqIA polymorphism and early onset alcohol use disorders.

Schuckit MA; Smith TL; Danko GP; Pierson J; Trim R; Nurnberger J et al. A comparison of factors associated with substanceance Induced versus independent depressions. Journal of Studies on Alcohol and Drugs 68(6): 805-812, 2007. (33 refs.)

Objective: This article expands on the results from a 1997 report from the Collaborative Study on the Genetics of Alcoholism (COGA), using a new phase of the protocol to evaluate the prevalence and characteristics of substance-induced and independent major depressive episodes (MDEs) in a population of alcoholics and nonalcoholics. Method: Data were evaluated from Phase II of the six-center-wide COGA investigation using information gathered beginning in January 1997. Data were generated through face-to-face evaluations using the updated version of the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA-II) interview, with distinctions between substance-induced and independent MDEs based on the chronology of development of full depressive syndromes. The analyses focused on the 2,548 men and women who were divided into 351 individuals who had only an independent MDE (Group 1), 238 subjects who experienced only substance-induced MDEs, and 1,959 individuals with no MDE history. Results: The two MDE groups were similar in age, marital status, and religion; but those with substance-induced depressions (Group 2) were more likely to be original alcoholic probands, be males, be nonwhite, and have less education. They were also more likely to have alcohol, drug, or antisocial personality diagnoses and to report higher maximum drinks. In addition, only Group 2 subjects reported an elevated family history of alcohol diagnoses compared with the nondepressed Group 3. Subjects with independent MDEs were different from the comparison Group 3 regarding the family histories of independent MDEs. However, symptoms during the worst depressive episode were quite similar across Groups 1 and 2. Conclusions: This study corroborates a high rate of substance-induced MDEs among alcoholics, with these disorders explaining about half of the lifetime depressive episodes. The results also support the validity of the distinction between substance-induced and independent depressions regarding external validators of gender, substance-use patterns, and family histories of independent MDEs.

Sher KJ; Wood MD. Subjective effects of alcohol. Part II. IN: Earleywine M, ed. Mind-Altering Drugs: The Science of Subjective Experience. New York: Oxford University Press, 2005. pp. 135-153. (124 refs.)

This chapter is the second of two dealing with alcohol. The focus is upon individual differences as influences and factors in determining the subjective effects of alcohol. Two domains are reviewed. One is genetics, aspects addressed include a family history of alcoholism, the effects on stressed and non-stressed individuals, and candidate genes. Personality is the other domain considered, with discussion of personality traits such as impulsivity, alcohol expectancies, cognitive functioning,

Sher L. The serotonin transporter gene and alcoholism: The two pathways to suicidal behavior. (letter). Medical Hypotheses 69(1): 232-232, 2007. (9 refs.)

Sliwerska E; Meng F; Speed TP; Jones EG; Bunney WE; Akil H et al. SNPs on Chips: The hidden genetic code in expression arrays. Biological Psychiatry 61(1): 13-16, 2007. (16 refs.)

Gene expression microarray analysis in postmortem brains is one of the fastest growing fields of psychiatric research. Here we show that common polymorphisms (SNPs) present on probe sets can masquerade as significant "gene expression" differences. After first observing this artifact in the Catechol-O-methyl transferase (COMT) gene, we replicate the finding in two additional genes predicted to show this artifact. Many Affymetrix chips contain thousands of SNPs that are both common and in the central probe region affecting hybridization, and thus have the potential to confound expression analysis.

Smith L; Watson M; Gates S; Ball D; Foxcroft D. Meta-analysis of the association of the Taq1A polymorphism with the risk of alcohol dependency: A HuGE gene-disease association review. American Journal of Epidemiology 167(2): 125-138, 2008. (98 refs.)

The human dopamine 2 receptor Taq1A allele has been implicated as a vulnerability factor for alcohol dependence in a number of studies and reviews. To determine whether this allele is associated with alcoholism, the authors conducted a Human Genome Epidemiology review and meta-analysis. Forty-four studies with 9,382 participants were included. An odds ratio of 1.38 (95% confidence interval: 1.20, 1.58; heterogeneity, 50.5%) was found for the A1A1 + A1A2 versus the A2A2 genotype. Sensitivity analyses suggested lack of ethnic matching as a possible source of heterogeneity; a small, significant association was detected in studies with ethnic-matched controls (odds ratio = 1.26, 95% confidence interval: 1.02, 1.56; heterogeneity, 37%). Significant associations were also found in analyses restricted to studies reporting use of blinding and those with adequate screening of controls for alcohol dependency. For the A1A1 versus the A1A2 + A2A2 genotype, the odds ratio was 1.22 (95% confidence interval: 1.05, 1.43; heterogeneity, 0%). Sensitivity analyses on groups of studies reporting use of ethnic-matched controls and those that screened controls for alcohol dependency still showed significant associations. The relatively small effect for the association of the A1 allele, or another genetic variant linked to it, with alcohol dependence indicates a multigene causality for this complex disorder.

Stern MC; Conti DV; Siegmund KD; Corral R; Yuan JM; Koh WP et al. DNA repair single-nucleotide polymorphisms in colorectal cancer and their role as modifiers of the effect of cigarette smoking and alcohol in the Singapore Chinese Health Study. Cancer Epidemiology, Biomarkers & Prevention 16(11): 2363-2372, 2007. (51 refs.)

Recently, we reported that among Singapore Chinese, cigarette smoking and alcohol drinking were independent risk factors for colorectal cancer. Both tobacco smoking and alcohol use are plausible colorectal cancer risk factors, partly due to their ability to induce mutations in the colorectal lumen. In the present study, we investigated the role in colorectal cancer of single-nucleotide polymorphisms in five DNA repair gene,: XRCC1 (Arg(194)Trp and Arg(399)Gln), PARP (Val(762)Ala, Lys(940)Arg), XPD (ASP(312)Asn, LYS(751)Gln), OGG1 (Ser(326)Cys), and MGMT (Leu(84)Phe). We conducted this study within the Singapore Chinese Health Study, a population-based cohort of 63,257 middle-aged and older Singapore Chinese men and women enrolled between 1993 and 1998. Our study included 1,176 controls and 310 cases (180 colon and 130 rectum cancer). We observed a positive association between the PARP codon 940 Lys/Arg and Arg/Arg genotypes and colorectal cancer risk [odds ratio (OR), 1.8; 94% confidence interval (95% CI), 1.1-3.1], and an inverse association between the MGMT codon 84 Leu/Phe or Phe/Phe genotypes and colon cancer risk (OR, 0.6; 95% CI, 0.3-0.9), but not rectal cancer (test of heterogeneity by tumor site, P = 0.027). We observed evidence that XRCC1 may modify the effects of smoking (interaction P = 0.012). The effect of smoking among carriers of the Arg(194)-Gln(399) haplotype was OR = 0.7 (95% CI, 0.4-1.1), whereas, among carriers of the Trp(194)-Arg(399) haplotype, it was OR = 1.6 (95% CI, 1.1-2.5). We also observed a nonstatistically significant modification of XRCC1 on the effects of alcohol (P = 0.245). Whereas alcohol had no effect among carriers of the codon 194 Arg/Arg (OR, 1.0; 95% CI, 0.61.7) or Arg/Trp genotypes (OR, 1.1; 95% CI, 0.6-1.9), there was a positive association among carriers of the Trp/Trp genotype (OR, 2.8; 95% CI, 1.0-8.1). Our results support a role for reactive oxygen species as relevant genotoxins that may account for the effects of both smoking and alcohol on colorectal cancer risk.

Suzuki M; Tanaka S; Komatsu H; Nakane T; Sasaki N; Maruyama K et al. Evaluation of alcohol metabolism in humans using the non-invasive [C-13]-ethanol breath test -- influence of gender, Helicobacter pylori infection and polymorphism of alcohol-oxidizing enzymes. Alimentary Pharmacology & Therapeutics 24(Supplement 4): 177-181, 2006. (13 refs.)

Background: The [C-13]-ethanol breath test (EBT) has been proposed as a novel non-invasive laboratory test to detect the degradation of ethanol into CO2. However, this method has not yet been evaluated clinically. Aim: To investigate the factors that influence [C-13]-EBT. Methods Twenty-six healthy volunteers were instructed to drink 100 mL of beer (4 g ethanol) containing 100 mu L of [C-13]-ethanol. Breath samples were collected every 15 min before and after the intake of ethanol solution and (CO2)-C-13-enrichment was measured using mass spectrometry. CO2 excretion was then calculated, and the results were evaluated using kinetic parameters (T-max, C-max, AUC). Results: T-max (min) was significantly shorter in men than in women but not C-max and AUC. Infection with H. pylori had no impact on all kinetic parameters. Genetic alcohol dehydrogenase (ADH) polymorphisms did not affect (CO2)-C-13 excretion, but C-max (11.1 +/- 3.4% dose/h, n = 16) and AUC (10.5 +/- 3.4% dose) were slightly increased in aldehyde dehydrogenase (ALDH)-deficient individuals (heterozygote of ALDH2*2) (13.2 +/- 3.2 and 12.9 +/- 4.5, respectively; n = 10). Conclusions: [C-13]-EBT is capable of assessing the metabolic processing of 100 mL beer in a non-invasive way. Kinetic parameters are partially influenced by ALDH polymorphism but not by gender, H. pylori infection or ADH polymorphism.

Szczepankiewicz A; Dmitrzak-Weglarz M; Skibinska M; Slopien A; Leszczynska-Rodziewicz A; Czerski P et al. Study of dopamine receptors genes polymorphisms in bipolar patients with comorbid alcohol abuse. Alcohol and Alcoholism 42(2): 70-74, 2007. (56 refs.)

Alcoholism is present in similar to 40-60% of bipolar patients. This comorbidity between bipolar disorder and alcoholism is high and may result from existence of common genetic factors for the two disorders. In both disorders, dysregulation of the dopaminergic neurotransmission had been implicated. Association analyses revealed several candidate genes acting in the dopaminergic pathway and polymorphisms in those genes that might be associated with both disorders. Aim: The aim of this study was to analyse possible relationship between polymorphisms in the dopaminergic pathway genes (one SNP for each dopamine receptor gene 1-4) and alcohol abuse comorbidity in bipolar patients. Methods: We analysed 317 patients with bipolar disorder. In this group, 42 patients were diagnosed with alcohol abuse. The diagnosis was made for each patient by at least two psychiatrists, using structured clinical interviews for DSM-IV Axis I disorders (SCID). The control group consisted of 350 subjects. We performed RFLP analysis of polymorphisms in four genes: DRD1, DRD2, DRD3, and DRD4. Results: We have not found association of any of the analysed polymorphisms in the dopamine genes in the group of bipolar patients with comorbid alcohol abuse as compared to the control group. In the male group of bipolar patients with comorbid alcohol abuse, we also have not observed any significant differences between the patients and the control subjects. Conclusion: Our findings suggest that the analysed polymorphisms of the dopamine genes polymorphisms may not be involved in the shared genetic vulnerability to both, bipolar disorder, and alcohol abuse.

Taylor JE; James LM; Reeves MD; Bobadilla L. The Florida State Twin Registry: Research aims and design. Twin Research and Human Genetics 9(6): 958-962, 2006. (29 refs.)

Relatively little is known about the relationship of most personality disorders to executive cognitive functioning despite their associations with frontal cortex activity. Research on genetic influence is lacking for most personality disorders, and research on genetic influences associated with executive cognitive functioning is sparse and mixed. The Florida State Twin Registry was created to conduct a pilot twin study aimed at examining genetic influence on personality disorders and executive cognitive functioning. Measures included structured clinical interviews for symptoms and diagnoses of personality disorders (borderline, histrionic, narcissistic, antisocial, obsessive-compulsive, avoidant, and dependent), depression, substance abuse/dependence, anxiety disorders, and eating disorders. The Wisconsin Card Sorting Test and the Stroop Color-Word Test were administered to assess executive cognitive functioning. Self-report questionnaires were included to assess maladaptive personality traits. Data sharing and future directions for growing the Florida State Twin Registry are discussed.

Terry MB; Knight JA; Zablotska L; Wang Q; John EM; Andrulis IL et al. Alcohol metabolism, alcohol intake, and breast cancer risk: A sister-set analysis using the Breast Cancer Family Registry. Breast Cancer Research and Treatment 106(2): 281-288, 2007. (37 refs.)

Moderate alcohol intake has been consistently associated with a modest (30-50%) increase in breast cancer risk, but it remains unclear if certain individuals have higher susceptibility to the harmful effects of alcohol intake. Individuals differ in their ability to metabolize alcohol through genetic differences in alcohol dehydrogenase (ADH), the enzyme that catalyzes the oxidation of approximately 80% of ethanol to acetaldehyde, a known carcinogen. Using data from the Breast Cancer Family Registry (n = 811 sister sets), we examined whether sisters with breast cancer differ with respect to alcohol consumption and alcohol metabolism (measured by polymorphisms in ADH1B and ADH1C) compared to their sisters without breast cancer. Neither alcohol drinking nor alcohol metabolizing ADH1B and ADH1C genotypes were associated with breast cancer risk. However, only 19% and 42% of sisters were discordant by ADH1B and ADH1C, respectively, and even fewer were discordant by both genotype and alcohol intake, making it difficult to detect differences if they existed.

Tsankova N; Renthal W; Kumar A; Nestler EJ. Epigenetic regulation in psychiatric disorders. (review). Nature Reviews. Neuroscience 8(5): 355-367, 2007. (109 refs.)

Many neurological and most psychiatric disorders are not due to mutations in a single gene; rather, they involve molecular disturbances entailing multiple genes and signals that control their expression. Recent research has demonstrated that complex 'epigenetic' mechanisms, which regulate gene activity without altering the DNA code, have long-lasting effects within mature neurons. This review summarizes recent evidence for the existence of sustained epigenetic mechanisms of gene regulation in neurons that have been implicated in the regulation of complex behaviour, including abnormalities in several psychiatric disorders such as depression, drug addiction and schizophrenia.

van der Zwaluw CS; van den Wildenberg E; Wiers RW; Franke B; Buitelaar J; Sebolte RHJ et al. Polymorphisms in the mu-opioid receptor gene (OPRM1) and the implications for alcohol dependence in humans. Pharmacogenomics 8(10): 1427-1436, 2007. (76 refs.)

Twin and adoption studies have shown that alcohol dependence contains a substantial genetic component. In attempts to identify the genetic factors involved, association studies have linked the opioid system to alcohol dependence, with a main focus on the OPRM1 gene encoding the mu-opioid receptor. Our aim was to conduct a systematic review of the literature on the associations between polymorphisms in OPRM1 and alcohol dependence. We addressed findings of 12 studies that met our inclusion criteria. All studies employed a case-control design and included alcohol dependence as a dependent outcome measure. Our review showed that clinical studies do not unequivocally support an association between polymorphisms in OPRM1 and alcohol dependence. Factors that complicate genetic research on alcohol dependence, such as gene-environment interaction, and genetic and clinical heterogeneity, are discussed.

Volk HE; Scherrer JF; Bucholz KK; Todorov A; Heath AC; Jacob T et al. Evidence for specificity of transmission of alcohol and nicotine dependence in an offspring of twins design. Drug and Alcohol Dependence 87(2/3): 225-232, 2007. (47 refs.)

Alcohol dependence (AD) and nicotine dependence (ND) have been shown to co-occur. Results from twin studies implicate the role of genetics in the etiology of both ND and AD with substantial, yet incomplete, overlap. To test for specificity of transmission of AD and ND in an offspring of twins sample we analyzed data from a study of adolescent and adult offspring of twin fathers ascertained from the Vietnam Era Twin Registry. This sample consists of 1213 twin fathers, 862 biologic or rearing mothers, and 1270 offspring. Offspring were allocated to one of four risk groups for AD based on twin fathers' zygosity and father's and cotwins AD history. Offspring DSM-IV AD and ND were measured by structured diagnostic interview. Paternal AD and ND were significantly associated with offspring AD and ND, respectively. Bivariate probit regression results suggest specificity for transmission of AD and ND. This remained constant after controlling for offspring demographics and psychopathology and maternal AD and ND. Despite the substantial genetic overlap between the two disorders, there is evidence for genetic effects specific for AD and ND.

Weinshenker D. Special addiction issue editorial. (editorial). Biochemical Pharmacology 75(1): 1-1, 2008. (6 refs.)

This special issue considers drug therapy for drug and alcohol depenence in light of genetic factors.

Westermeyer J; Bennett L; Thuras P; Yoon G. Substance use disorder among adoptees: A clinical comparative study. American Journal of Drug and Alcohol Abuse 33(3): 455-466, 2007. (30 refs.)

Goals of the study were to assess whether adoptees in treatment for Substance Use Disorder (SUD) (1) were over-, equi-, or under-represented in a clinical sample of patients with (SUD) and (2) differed demographically and clinically from non-adoptees with SUD. Sample consisted of 608 patients in two alcohol-drug treatment programs. Data collection included the Childhood Problems Scale, the Minnesota Substance Abuse Problem Scale, and the Minnesota Substance Abuse Treatment Questionnaire, and the Michigan Assessment-Screening Test/Alcohol-Drug. Findings showed that the prevalence of adoptees among SUD patients was 14 times higher than expected (95% Confidence Interval, 10 to 18 times). Adoptees reported childhood histories similar to those of non-adoptees with "any parental SUD", but they more closely resembled non-adoptees without parental SUD in regard to SUD severity and SUD treatment. Conclusion is that adoptees and their adoptive families should be alert to the increased risk of SUD among adoptees. Clinicians can expect that adoptees should manifest milder levels of SUD morbidity, similar to "non-heredity" SUD.

Westermeyer J; Bennett L; Thuras P; Yoon G. Substance use disorder among adoptees: A clinical comparative study. American Journal of Drug and Alcohol Abuse 33(3): 455-466, 2007. (30 refs.)

Goals of the study were to assess whether adoptees in treatment for Substance Use Disorder (SUD) (1) were over-, equi-, or under-represented in a clinical sample of patients with (SUD) and (2) differed demographically and clinically from non-adoptees with SUD. Sample consisted of 608 patients in two alcohol-drug treatment programs. Data collection included the Childhood Problems Scale, the Minnesota Substance Abuse Problem Scale, and the Minnesota Substance Abuse Treatment Questionnaire, and the Michigan Assessment-Screening Test/Alcohol-Drug. Findings showed that the prevalence of acloptees among SUD patients was 14 times higher than expected (95% Confidence Interval, 10 to 18 times). Adoptees reported childhood histories similar to those of non-adoptees with "any parental SUD", but they more closely resembled non-adoptees without parental SUD in regard to SUD severity and SUD treatment. Conclusion is that adoptees and their adoptive families should be alert to the increased risk of SUD among adoptees. Clinicians can expect that adoptees should manifest milder levels of SUD morbidity, similar to "non-heredity" SUD.

Wronski M; Skrok-Wolska D; Samochowiec J; Ziolkowski M; Swiecicki L; Bienkowski P et al. Perceived intensity and pleasantness of sucrose taste in male alcoholics. Alcohol and Alcoholism 42(2): 75-79, 2007. (43 refs.)

Aims: The aim of the present study was to evaluate a possible relationship between taste responses to sweet solutions and alcoholic status. Methods: The rated intensity and pleasantness of sucrose taste was compared in male alcoholics (n = 45) and nonalcoholic controls (n = 33). Results: The rated intensity, but not pleasantness, of water taste (0% sucrose) was higher in the alcoholics. The two groups did not differ with respect to the rated intensity or pleasantness of sucrose solutions (1-30%). The proportion of sweet-likers, i.e. subjects rating 30% sucrose as most pleasant, was similar in both groups (the controls: 57.6%, the alcoholics: 62.2%). A subgroup of alcoholics with a paternal history of alcoholism (n = 22) rated the highest sucrose concentration as more pleasant compared to alcoholics without alcoholic fathers. The proportion of sweet-likers among the alcoholics with a paternal history of alcoholism (77.3%) was significantly higher than that found in the alcoholics without a familial history of alcoholism (47.8%). Conclusions: The present results suggest the following: (i) alcohol dependence is not associated with any major alterations in taste responses to sucrose solutions, (ii) sweet liking is a phenotypic marker of male alcoholics with a paternal history of alcoholism.

Yang M; Tsuang J; Wan YJY. A haplotype analysis of CYP2E1 polymorphisms in relation to alcoholic phenotypes in Mexican Americans. Alcoholism: Clinical and Experimental Research 31(12): 1991-2000, 2007. (74 refs.)

Background: Studies regarding the association between the 4 polymorphisms of CYP2E1 (CYP2E1*1D, *5B, *6, and *1B) and alcoholism are inconsistent and inconclusive. The purpose of the present study was to clarify previously discordant studies by haplotype analysis in the Mexican American population. Methods: The 4 polymorphisms of CYP2E1 were studied in 334 alcoholics and 365 controls. Genotype, allele, and haplotype frequency comparisons between alcoholics and controls were assessed. Patterns of linkage disequilibrium (LD) at CYP2E1 were determined. Reconstructed haplotypes were tested for associations with clinical phenotypes (age onset of drinking, Maxdrinks, and smoking status). Results No significant associations between the 4 polymorphisms of CYP2E1 and alcoholism were revealed by single allele tests. High LD was found between the CYP2E1 c2 and C alleles in Mexican Americans. Eleven haplotypes were present in the 699 participants. The 6 main haplotypes with frequencies higher than 1% made up 97% of the total halpotypes. The frequency of subjects carrying H6 (1C-c2-C-A2) was significantly higher in alcoholics than in controls (p = 0.0001). In contrast, the frequencies of H7 (1C-c2-C-A1) and H10 (1C-c2-D-A1) were significantly lower in alcoholics than in controls (p = 0.0072 for H7 and p = 0.0407 for H10). The frequency of H6 was significantly higher in alcoholics who had late onset of drinking than in nonalcoholic controls. Furthermore, the frequencies of H6 haplotype were also consistently higher in groups who had high number of maximum drinks (9 to 32 drinks) than in controls. When smokers are excluded, the frequencies of H6, H7, and H9 (1C-c2-D-A2) showed statistically significant differences between alcoholics and controls (p < 0.05). Moreover, the association between H6 and alcoholism become more robust when smokers are excluded. Furthermore, the frequency of H1 (1C-c1-D-A2) in alcoholic-smokers was much higher than in alcoholic-nonsmokers (p = 0.0028). In contrast, alcoholic-smokers carried less H2 (1C-c1-D-A1) in comparison with alcoholic-nonsmokers (p = 0.0417). The H3 (1D-c2-C-A2) frequency in alcoholic-smokers was much lower than in alcoholic-nonsmokers (p = 0.0042) and control-smokers (p = 0.0363). Conclusion Our data demonstrate that carrying haplotype H6 might enhance susceptibility to developing alcoholism, but possessing the H7 or H10 haplotype appears to decrease this susceptibility. The H6, H7, and H9 haplotypes may play certain roles in different clinical phenotypes in Mexican American alcoholics. In addition, our data suggest that the H1, H2, and H3 haplotypes are associated with alcohol drinking and smoking. These results support that haplotype analysis is much more informative than single allele analysis. Our findings clearly indicate the importance of H6 haplotype in alcohol drinking in Mexican Americans.

Zammit S; Spurlock G; Williams H; Norton N; Williams N; O'Donovan MC et al. Genotype effects of CHRNA7, CNRI and COMT in schizophrenia: interactions with tobacco and cannabis use. British Journal of Psychiatry 191: 402-407, 2007. (42 refs.)

Background: Genetic variations might modify associations between schizophrenia and cannabis or tobacco use. Aims: To examine whether variants within the cannabinoid receptor (CNRI) and alpha(7) nicotinic receptor (CHRNA7) genes are associated with schizophrenia, and whether these effects vary according to cannabis or tobacco use. We also examined a putative interaction between cannabis and Val(158)Met within the catechol-O-methyltransferase gene (COMT). Method Genotype effects of CHRNA7 and CNRI were studied in a case-control sample of 750 individuals with schizophrenia and 688 controls, with interactions for these genes studied in small subsamples. A case-only design of 493 of the schizophrenia group was used to examine interactions between cannabis use and COMT Results There was no evidence of association between schizophrenia and CNRI (OR=0.97,95% Cl 0.82-1.13) or CHRNA7 (OR=1.07,95% Cl 0.77-1.49) genotypes, or of interactions between tobacco use and CHRNA7, or cannabis use and CNRI or COMT genotypes. Conclusions: Neither CNRI nor CHRNA7 variation appears to alter the risk of schizophrenia. Furthermore, our results do not support the presence of different effects of cannabis use on schizophrenia according to variation within COMT.

CORK Bibliography: Genetics and Alcohol Use

96 citations. January 2007 to present

Prepared: March 2008

Agrawal A; Dick DM; Bucholz KK; Madden PAF; Cooper ML; Sher KJ et al. Drinking expectancies and motives: A genetic study of young adult women. Addiction 103(2): 194-204, 2008. (50 refs.)

Andersson C; Johnsson KO; Berglund M; Ojehagen A. Alcohol involvement in Swedish University freshmen related to gender, age, serious relationship and family history of alcohol problems. Alcohol and Alcoholism 42(5): 448-455, 2007. (45 refs.)

Ball D. Genetics of addiction. Psychiatry 5(12): 446-448, 2006. (14 refs.)

Barnow S; Schuckit M; Smith T; Spitzer C; Freyberger HJ. Attention problems among children with a positive family history of alcohol abuse or dependence and controls: Prevalence and course for the period from preteen to early teen years. European Addiction Research 13(1): 1-5, 2007. (59 refs.)

Biederman J Petty CR Wilens TE Fraire MG Purcell CA Mick E et al. Familial risk analyses of attention deficit hyperactivity disorder and substance use disorders. American Journal of Psychiatry 165(1): 107-115, 2008. (37 refs.)

Bleich S; Bonsch D; Rauh J; Bayerlein K; Fiszer R; Frieling H et al. Association of the long allele of the 5-httlpr polymorphism with compulsive craving in alcohol dependence. Alcohol and Alcoholism 42(6): 509-512, 2007. (31 refs.)

Button TMM; Rhee SH; Hewitt JK; Young SE; Corley RP; Stallings MC. The role of conduct disorder in explaining the comorbidity between alcohol and illicit drug dependence in adolescence. Drug and Alcohol Dependence 87(1): 46-53, 2007. (44 refs.)

Chen YJ; Chen C; Wu DC; Lee CH; Wu CI; Lee JM et al. Interactive effects of lifetime alcohol consumption and alcohol and aldehyde dehydrogenase polymorphisins on esophageal cancer risks. International Journal of Cancer 119(12): 2827-2831, 2006. (32 refs.)

Clarimon J; Gray RR; Williams LN; Enoch MA; Robin RW; Albaugh B; Singleton A et al. Linkage disequilibrium and association analysis of alpha-synuclein and alcohol and drug dependence in two American Indian populations. Alcoholism: Clinical and Experimental Research 31(4): 546-554, 2007. (43 refs.)

Cosci F; Schruers KRJ; Abrams K; Griez EJL. Alcohol use disorders and panic disorder: A review of the evidence of a direct relationship. (review). Journal of Clinical Psychiatry 68(6): 874-880, 2007. (39 refs.)

Criado JR; Ehlers CL. Electrophysiological responses to affective stimuli in southwest California Indians: Relationship to alcohol dependence. Journal of Studies on Alcohol and Drugs 68(6): 813-823, 2007. (97 refs.)

Dai X; Thavundayil J; Santella S; Gianoulakis C. Response of the HPA-axis to alcohol and stress as a function of alcohol dependence and family history of alcoholism. Psychoneuroendocrinology 32(3): 293-305, 2007. (78 refs.)

Davis LL; Frazier EC; Gaynes BN; Trivedi MH; Wisniewski SR; Fava M et al. Are depressed outpatients with and without a family history of substance use disorder different? A baseline analysis of the STAR*D cohort. Journal of Clinical Psychiatry 68(12): 1931-1938, 2007. (31 refs.)

Davis TJ; de Fiebre CM. Alcohol's actions on neuronal nicotinic acetylcholine receptors. Alcohol Research and Health 29(3): 179-185, 2006. (31 refs.)

Dick DM. Identification of genes influencing a spectrum of externalizing psychopathology. Current Directions in Psychological Science 16(6): 331-335, 2007. (23 refs.)

Dick DM; Agrawal A; Wang JC; Hinrichs A; Bertelsen S; Bucholz KK et al. Alcohol dependence with comorbid drug dependence: Genetic and phenotypic associations suggest a more severe form of the disorder with stronger genetic contribution to risk. Addiction 102(7): 1131-1139, 2007. (46 refs.)

Dick DM; Pagan JL; Holliday C; Viken R; Pulkkinen L; Kaprio J et al. Gender differences in friends' influences on adolescent drinking: A genetic epidemiological study. Alcoholism: Clinical and Experimental Research 31(12): 2012-2019, 2007. (28 refs.)

Dodd PR; Buckley ST; Eckert AL; Foley PF; Innes DJ. Genes and gene expression in the brains of human alcoholics. Annals of the New York Academy of Sciences. Cellular and molecular mechanisms 1074: 104-115, 2006. (32 refs.)

Doran N; Myers MG; Luczak SE; Carr LG; Wall TL. Stability of heavy episodic drinking in Chinese- and Korean-American college students: Effects of ALDH2 gene status and behavioral undercontrol. Journal of Studies on Alcohol and Drugs 68(6): 789-797, 2007. (65 refs.)

Drgon T; D'Addario C; Uhl GR. Linkage disequilibrium, haplotype and association studies of a chromosome 4 GABA receptor gene cluster: Candidate gene variants for addictions. American Journal of Medical Genetics, Part B. Neuropsychiatric Genetics 141B(8): 854-860, 2006. (35 refs.)

Ehlers CL; Phillips E. Association of EEG alpha variants and alpha power with alcohol dependence in Mexican American young adults. Alcohol 41(1): 13-20, 2007. (65 refs.)

Enoch MA. Genetic and environmental influences on the development of alcoholism: Resilience vs. risk. Annals of the New York Academy of Sciences: Resilience in Children 1094: 193-201, 2006. (41 refs.)

Faraone SV; Adamson JJ; Wilens TE; Monuteaux MC; Biederman J. Deriving phenotypes for molecular genetic studies of substance use disorders: A family study approach. Drug and Alcohol Dependence 88(2/3): 244-250, 2007. (51 refs.)

Fowler T; Lifford K; Shelton K; Rice F; Thapar A; Neale MC et al. Exploring the relationship between genetic and environmental influences on initiation and progression of substance use. Addiction 102(3): 413-422, 2007. (43 refs.)

Fowler T; Shelton K; Lifford K; Rice F; McBride A; Nikolov I. Genetic and environmental influences on the relationship between peer alcohol use and own alcohol use in adolescents. Addiction 102(6): 894-903, 2007. (48 refs.)

Gao CM; Takezaki T; Wu JZ; Chen MB; Liu YT; Ding IH et al. CP2E1 Rsa I polymorphism impacts on risks of colorectal cancer association with smoking and alcohol drinking. World Journal of Gastroenterology 13(43): 5725-5730, 2007. (44 refs.)

Gass JT; Olive MF. Glutamatergic substrates of drug addiction and alcoholism. (review). Biochemical Pharmacology 75(1): 218-265, 2008. (906 refs.)

Gemma S; Vichi S; Testai E. Metabolic and genetic factors contributing to alcohol induced effects and fetal alcohol syndrome. (review). Neuroscience and Biobehavioral Reviews 31(2): 221-229, 2007. (53 refs.)

Goodman A. Neurobiology of addiction - An integrative review. (review). Biochemical Pharmacology 75(1): 266-322, 2008. (1118 refs.)

Grucza RA; Bierut LJ. Co-occurring risk factors for alcohol dependence and habitual smoking: Update on findings from the Collaborative Study on the Genetics of Alcoholism. Alcohol Research and Health 29(3): 172-178, 2006. (30 refs.)

Guerrini I; Thomson AD; Gurling HD. The importance of alcohol misuse, malnutrition and genetic susceptibility on brain growth and plasticity. (review). Neuroscience and Biobehavioral Reviews 31(2): 212-220, 2007. (124 refs.)

Guo G; Wilhelmsen K; Hamilton N. Gene-lifecourse interaction for alcohol consumption in adolescence and young adulthood: Five monoamine genes. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 144B(4): 417-423, 2007. (61 refs.)

Harris KM; Halpern CT; Smolen A; Haberstick BC. The National Longitudinal Study of Adolescent Health twin data. Twin Research and Human Genetics 9(6): 988-997, 2006. (23 refs.)

Heilig M. IMAGEN: Implications for addiction science and science policy. (editorial). Addiction 102(11): 1699-1700, 2007. (19 refs.)

Heinz A; Friedel E; Muller DJ; Puls I; Wrase J. Genetic research with intermediate phenotypes: Phenocopies, perspectives and pitfalls. (editorial). Addiction 102(11): 1696-1697, 2007. (18 refs.)

Hill SY; Kostelnik B; Holmes B; Goradia D; McDermott M; Diwadkar V et al. FMRI BOLD response to the eyes task in offspring from multiplex alcohol dependence families. Alcoholism: Clinical and Experimental Research 31(12): 2028-2035, 2007. (37 refs.)

Hill SY; Muddasani S; Prasad K; Nutche J; Steinhauer SR; Scanlon J et al. Cerebellar volume in offspring from multiplex alcohol dependence families. Biological Psychiatry 61(1): 41-47, 2007. (58 refs.)

Hillemacher T; Wilhelm J; von Ahsen N; Bayerlein K; Frieling H; Kornhuber J et al. Obsessive-compulsive alcohol craving is not associated with Apolipoprotein E genotype. Psychiatric Genetics 16(6): 231-232, 2006. (4 refs.)

Hiraki A; Matsuo K; Wakai K; Suzuki T; Hasegawa Y; Tajima K. Gene-gene and gene-environment interactions between alcohol drinking habit and polymorphisms in alcohol-metabolizing enzyme genes and the risk of head and neck cancer in Japan. Cancer Science 98(7): 1087-1091, 2007. (22 refs.)

Hopfer C. Study boosts evidence on linkage regions associated with alcoholism. (editorial). European Journal of Human Genetics 14(12): 1231-1232, 2006. (10 refs.)

Howell LL; Kimmel HL. Monoamine transporters and psychostimulant addiction. (review). Biochemical Pharmacology 75(1): 196-217, 2008. (355 refs.)

Jensen MK; Mukamal KJ; Overvad K; Rimm EB. Alcohol consumption, TaqIB polymorphism of cholesteryl ester transfer protein, high-density lipoprotein cholesterol, and risk of coronary heart disease in men and women. European Heart Journal 29(1): 104-112, 2008. (45 refs.)

Kaufman J; Yang BZ; Douglas-Palumberi H; Crouse-Artus M; Lipschitz D; Krystal JH et al. Genetic and environmental predictors of early alcohol use. Biological Psychiatry 61(11): 1228-1234, 2007. (47 refs.)

Kendler KS; Kuo PH; Webb BT; Kalsi G; Neale MC; Sullivan PF et al. A joint genomewide linkage analysis of symptoms of alcohol dependence and conduct disorder. Alcoholism: Clinical and Experimental Research 30(12): 1972-1977, 2006. (19 refs.)

Kim J-W; Park CS; Hwang J-W; Shin M-S; Hong K-E; Cho S-C et al. Clinical and genetic characteristics of Korean male alcoholics with and without attention deficit hyperactivity disorder. Alcohol and Alcoholism 41(4): 407-411, 2006. (49 refs.)

Klein TA; Neumann J; Reuter M; Hennig J; von Cramon DY; Ullsperger M. Genetically determined differences in learning from errors. Science 318(5856): 1642-1645, 2007. (28 refs.)

Knopik VS; Heath AC; Jacob T; Slutske WS; Bucholz KK; Madden PAF et al. Maternal alcohol use disorder and offspring ADHD: Disentangling genetic and environmental effects using a children-of-twins design. Psychological Medicine 36(10): 1461-1471, 2006. (56 refs.)

Koehnke MD. Approach to the genetics of alcoholism: A review based on pathophysiology. (review). Biochemical Pharmacology 75(1): 160-177, 2008. (238 refs.)

Kohnke MD; Kolb W; Lutz U; Maurer S; Batra A. The serotonin transporter promotor polymorphism 5-HTTLPR is not associated with alcoholism or severe forms of alcohol withdrawal in a German sample. (letter). Psychiatric Genetics 16(6): 227-228, 2006. (4 refs.)

Koob GF. Alcoholism, corticotropin-releasing factor, and molecular genetic allostasis. (editorial). Biological Psychiatry 63(2): 137-138, 2008. (10 refs.)

Larkins JM; Sher KJ. Family history of alcoholism and the stability of personality in young adulthood. Psychology of Addictive Behaviors 20(4): 471-477, 2006. (48 refs.)

Laucht M; Becker K; Blomeyer D; Schmidt MH. Novelty seeking involved in mediating the association between the dopamine D4 receptor gene Exon III polymorphism and heavy drinking in male adolescents: Results from a high-risk community sample. Biological Psychiatry 61(1): 87-92, 2007. (49 refs.)

Le Strat Y; Ramoz N; Pickering P; Burger V; Boni C; Aubin HJ. The 3' part of the dopamine transporter gene DAT1/SLC6A3 is associated with withdrawal seizures in patients with alcohol dependence. Alcoholism: Clinical and Experimental Research 32(1): 27-35, 2008. (69 refs.)

Li TK; Volkow ND; Baler RD; Egli M. The biological bases of nicotine and alcohol co-addiction. Biological Psychiatry 61(1): 1-3, 2007. (37 refs.)

Loza AJM; Iglesias MTR; Diaz IP; Castellanos SC; Andrade CG; Mora MEM et al. Association of alcohol-metabolizing genes with alcoholism in a Mexican Indian (Otomi) population. Alcohol 39(2): 73-79, 2006. (56 refs.)

Luo XG; Kranzler HR; Zuo LJ; Wang S; Schork NJ; Gelernter J. Multiple ADH genes modulate risk for drug dependence in both African- and European-Americans. Human Molecular Genetics 16(4): 380-390, 2007. (54 refs.)

Lyons MJ; Schultz M; Neale M; Brady K; Eisen S; Toomey R et al. Specificity of familial vulnerability for alcoholism versus major depression in men. Journal of Nervous and Mental Disease 194(11): 809-817, 2006. (24 refs.)

MacKillop J; Menges DP; McGeary JE; Lisman SA. Effects of craving and DRD4 VNTR genotype on the relative value of alcohol: an initial human laboratory study. Behavioral and Brain Functions 3: article 11, 2007. (85 refs.)

Matsuo K; Hiraki A; Hirose K; Ito H; Suzuki T; Wakai K et al. Impact of the alcohol-dehydrogenase (ADH) 1C and ADH1B polymorphisms on drinking behavior in nonalcoholic Japanese. Human Mutation 28(5): 506-510, 2007. (33 refs.)

Miles MF; Williams RW. Meta-analysis for microarray studies of the genetics of complex traits. Trends in Biotechnonology 25(2): 45-47, 2007. (10 refs.)

Montane-Jaime K; Moore S; Shafe S; Joseph R; CrookSa H; Carr L et al. ADH1C*2 allele is associated with alcohol dependence and elevated liver enzymes in Trinidad and Tobago. Alcohol 39(2): 81-86, 2006. (34 refs.)

Munafo MR; Matheson IJ; Flint J. Association of the DRD2 gene Taq1A polymorphism and alcoholism: A meta-analysis of case-control studies and evidence of publication bias. Molecular Psychiatry 12(5): 454-461, 2007. (61 refs.)

Neumark YD; Lopez-Quintero C; Grinshpoon A; Levinson D. Alcohol drinking patterns and prevalence of alcohol-abuse and dependence in the Israel national health survey. Israel Journal of Psychiatry and Related Sciences 44(2): 126-135, 2007. (47 refs.)

Nurnberger JI; Bierut LJ. Seeking the connections: Alcoholism and our genes. Scientific American 296(4): 46-53, 2007. (3 refs.)

Ocaranza P; Quintanilla ME; Tampier L; Karahanian E; Sapag A; Israel Y. Gene therapy reduces ethanol intake in an animal model of alcohol dependence. Alcoholism: Clinical and Experimental Research 32(1): 52-57, 2008. (42 refs.)

Rangaswamy M; Jones KA; Porjesz B; Chorlian DB; Padmanabhapillai A; Kamarajan C et al. Delta and theta oscillations as risk markers in adolescent offspring of alcoholics. (review). International Journal of Psychophysiology 63(1): 3-15, 2007. (118 refs.)

Rasmussen F; Kark M; Tholin S; Karnehed N; Tynelius P. The Swedish Young Male Twins Study: A resource for longitudinal research on risk factors for obesity and cardiovascular diseases. Twin Research and Human Genetics 9(6): 883-889, 2006. (16 refs.)

Reuter M; Jeste N; Klein T; Hennig J; Goldman D; Enoch MA et al. Association of THR105Ile, a functional polymorphism of histamine N-methyltransferase (HNMT), with alcoholism in German Caucasians. Drug and Alcohol Dependence 87(1): 69-75, 2007. (36 refs.)

Rhea SA; Gross AA; Haberstick BC; Corley RP. Colorado Twin Registry. Twin Research and Human Genetics 9(6): 941-949, 2006. (26 refs.)

Rohsenow DJ; Miranda R; McGeary JE; Monti PM. Family history and antisocial traits moderate naltrexone's effects on heavy drinking in alcoholics. Experimental and Clinical Psychopharmacology 15(3): 272-281, 2007. (54 refs.)

Sakai JT; Hopfer CJ; Hartman C; Haberstick BC; Smolen A; Corley RP et al. Test of association between TaqIA A1 allele and alcohol use disorder phenotypes in a sample of adolescent patients with serious substance and behavioral problems. Drug and Alcohol Dependence 88(2/3): 130-137, 2007. (59 refs.)

Schuckit MA; Smith TL; Danko GP; Pierson J; Trim R; Nurnberger J et al. A comparison of factors associated with substanceance Induced versus independent depressions. Journal of Studies on Alcohol and Drugs 68(6): 805-812, 2007. (33 refs.)

Sher KJ; Wood MD. Subjective effects of alcohol. Part II. IN: Earleywine M, ed. Mind-Altering Drugs: The Science of Subjective Experience. New York: Oxford University Press, 2005. pp. 135-153. (124 refs.)

Sher L. The serotonin transporter gene and alcoholism: The two pathways to suicidal behavior. (letter). Medical Hypotheses 69(1): 232-232, 2007. (9 refs.)

Sliwerska E; Meng F; Speed TP; Jones EG; Bunney WE; Akil H et al. SNPs on Chips: The hidden genetic code in expression arrays. Biological Psychiatry 61(1): 13-16, 2007. (16 refs.)

Smith L; Watson M; Gates S; Ball D; Foxcroft D. Meta-analysis of the association of the Taq1A polymorphism with the risk of alcohol dependency: A HuGE gene-disease association review. American Journal of Epidemiology 167(2): 125-138, 2008. (98 refs.)

Szczepankiewicz A; Dmitrzak-Weglarz M; Skibinska M; Slopien A; Leszczynska-Rodziewicz A; Czerski P et al. Study of dopamine receptors genes polymorphisms in bipolar patients with comorbid alcohol abuse. Alcohol and Alcoholism 42(2): 70-74, 2007. (56 refs.)

Davis LL; Frazier EC; Gaynes BN; Trivedi MH; Wisniewski SR; Fava M et al. Are depressed outpatients with and without a family history of substance use disorder different? A baseline analysis of the STARD cohort. Journal of Clinical Psychiatry* 68(12): 1931-1938, 2007. (31 refs.)

Montane-Jaime K; Moore S; Shafe S; Joseph R; CrookSa H; Carr L et al. ADH1C2 allele is associated with alcohol dependence and elevated liver enzymes in Trinidad and Tobago. Alcohol* 39(2): 81-86, 2006. (34 refs.)