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Background: Adolescent drinking is an important public health concern, one that is influenced by both genetic and environmental factors. The functional variant rs1229984 in alcohol dehydrogenase 1B (ADH1B) has been associated at a genome-wide level with alcohol use disorders in diverse adult populations. However, few data are available regarding whether this variant influences early drinking behaviors and whether social context moderates this effect. This study examines the interplay between rs1229984 and peer drinking in the development of adolescent drinking milestones., Methods: One thousand five hundred and fifty European and African American individuals who had a full drink of alcohol before age 18 were selected from a longitudinal study of youth as part of the Collaborative Study on the Genetics of Alcoholism (COGA). Cox proportional hazards regression, with G × E product terms in the final models, was used to study 2 primary outcomes during adolescence: age of first intoxication and age of first DSM-5 alcohol use disorder symptom., Results: The minor A allele of rs1229984 was associated with a protective effect for first intoxication (HR = 0.56, 95% CI 0.41 to 0.76) and first DSM-5 symptom (HR = 0.45, 95% CI 0.26 to 0.77) in the final models. Reporting that most or all best friends drink was associated with a hazardous effect for first intoxication (HR = 1.81, 95% CI 1.62 to 2.01) and first DSM-5 symptom (HR = 2.17, 95% 1.88 to 2.50) in the final models. Furthermore, there was a significant G × E interaction for first intoxication (p = 0.002) and first DSM-5 symptom (p = 0.01). Among individuals reporting none or few best friends drinking, the ADH1B variant had a protective effect for adolescent drinking milestones, but for those reporting most or all best friends drinking, this effect was greatly reduced., Conclusions: Our results suggest that the risk factor of best friends drinking attenuates the protective effect of a well-established ADH1B variant for 2 adolescent drinking behaviors. These findings illustrate the interplay between genetic and environmental factors in the development of drinking milestones during adolescence., (Copyright © 2014 by the Research Society on Alcoholism.)

Background: Endophenotypes reflect more proximal effects of genes than diagnostic categories, hence providing a more powerful strategy in searching for genes involved in complex psychiatric disorders. There is strong evidence suggesting the P3 amplitude of the event-related potential (ERP) as an endophenotype for the risk of alcoholism and other disinhibitory disorders. Recent studies demonstrated a crucial role of corticotropin releasing hormone receptor 1 (CRHR1) in the environmental stress response and ethanol self-administration in animal models. The aim of the present study was to test the potential associations between single-nucleotide polymorphisms (SNPs) in the CRHR1 gene and the quantitative trait, P3 amplitude during the processing of visual target signals in an oddball paradigm, as well as alcohol dependence diagnosis., Methods: We analyzed a sample from the Collaborative Study on the Genetics of Alcoholism (COGA) comprising 1049 Caucasian subjects from 209 families (including 472 alcohol-dependent individuals). Quantitative transmission disequilibrium test (QTDT) and family-based association test (FBAT) were used to test the association, and false discovery rate (FDR) was applied to correct for multiple comparisons., Results: Significant associations (p < 0.05) were found between the P3 amplitude and alcohol dependence with multiple SNPs in the CRHR1 gene., Conclusions: Our results suggest that CRHR1 may be involved in modulating the P3 component of the ERP during information processing and in vulnerability to alcoholism. These findings underscore the utility of electrophysiology and the endophenotype approach in the genetic study of psychiatric disorders.

Background: Heavy drinking is associated with an increased number of sexual partners. This study examined the extent to which alcohol dependence and conduct disorder are associated with the number of sexual partners and membership in a risk group of having a high number of sexual partners (10 or more)., Methods: Data were obtained by personal interview from 601 relatives (aged 18 to 25 years) of alcohol-dependent probands who participated in the Collaborative Study on the Genetics of Alcoholism (COGA) project. Analyses examined the independent contribution of problem drinking (defined as having at least one symptom of DSM-IV alcohol dependence) and alcohol dependence, some conduct problems (defined as having at least one symptom of DSM-IV conduct disorder), conduct disorder, family status (defined as whether participant lived with both biological parents during childhood), educational attainment, gender, race, age at first intercourse, and age at time of interview to the number of sexual partners and to having 10 or more sexual partners., Results: After controlling for other variables, alcohol dependence, problem drinking, race, age at first intercourse, and age at time of interview were significantly associated with number of sexual partners. The risk for having 10 or more sexual partners rose substantially for those who were alcohol dependent (OR = 2.5, 1.3-4.5, p = 0.004) and those with conduct disorder (OR = 1.8, 1.0-3.3, p = 0.041) after controlling for other variables. There is also a trend toward problem drinking and some conduct problems being associated with the risk of having 10 or more sexual partners though this did not reach statistical significance., Conclusions: These analyses demonstrate that alcohol-dependent individuals and those with conduct disorder are at risk for increased number of sexual partners (10 or more). Sexually transmitted disease prevention efforts should target individuals with these two conditions to help decrease high risk sexual behaviors.

Background: There is an extensive and inconsistent literature on the association of the dopamine D2 receptor gene (DRD2) with alcohol dependence. Conflicting results have been attributed to differences in the severity of the alcohol dependence phenotype across studies, failure to exclude related disorders from comparison groups, and artifacts of population-stratification. Recently the genetic polymorphism most widely analyzed in DRD2, Taq1A, has been discovered to reside in a neighboring gene, ankyrin repeat and kinase domain containing 1 (ANKK1), located 10 kb downstream from DRD2., Methods: To more carefully characterize evidence for association across this region, we genotyped 26 single nucleotide polymorphisms (SNPs) spanning DRD2 and ANKK1 in a sample of 219 Caucasian families (n = 1,923) from the Collaborative Study on the Genetics of Alcoholism (COGA), making this the most extensive analysis to date of association between this region and alcohol dependence. We used family-based analyses robust to population-stratification, and we made use of rich phenotypic data to analyze alcohol dependence and subtypes hypothesized in the literature to be more directly influenced by DRD2., Results: We found that the evidence for association is strongest in the 5' linkage disequilibrium block of ANKK1 (that does not contain Taq1A), with weak evidence of association with a small number of SNPs in DRD2. The association in ANKK1 is strongest among the subsets of alcoholics with medical complications and with antisocial personality disorder., Conclusions: More extensive genotyping across DRD2 and ANKK1 suggests that the association with alcohol dependence observed in this region may be due to genetic variants in the ANKK1 gene. ANKK1 is involved in signal transduction pathways and is a plausible biological candidate for involvement in addictive disorders.

Background: Studies have found that genomic variation in the gene SNCA, which encodes the protein alpha-synuclein, may contribute to the variation in alcohol consumption in an inbred rat model of alcohol preference. Studies in humans have provided support for an association between SNCA and craving for alcohol., Methods: To examine the role of this gene in alcohol dependence and related phenotypes, 30 single nucleotide polymorphisms (SNPs) were genotyped across the SNCA gene in a sample of 219 multiplex alcoholic families of European American descent. Two phenotypes, alcohol dependence and alcohol craving, were analyzed using the pedigree disequilibrium test., Results: There was no evidence of association between any of the SNCA SNPs and alcohol dependence (p>or=0.13). In contrast, 8 SNPs provided evidence of association (p<0.05) with the phenotype of alcohol craving. Haplotype analysis further supported evidence of an association with alcohol craving; a haplotype encompassing SNPs in intron 4 through the region downstream of the gene was overtransmitted to cravers and a second haplotype was overtransmitted to noncravers., Conclusions: These results suggest that variation in SNCA contributes to alcohol craving, a common, although not uniform, feature of alcohol dependence.

Background: Alcohol dependence is a clinically and etiologically heterogeneous disorder. Accordingly, a variety of subtypes of alcohol-dependent individuals have been proposed, and multiple operational definitions of alcohol use, abuse, and dependence have been used in linkage analyses directed toward detecting genes involved in alcohol use and problems. Here, we develop quantitative phenotypes that characterize drinking patterns among both alcoholic and nonalcoholic subjects, and use these phenotypes in subsequent linkage analyses., Methods: More than 9000 individuals from alcoholic and control families were administered a semistructured interview and personality questionnaire as part of the initial stage of the Collaborative Study on the Genetics of Alcoholism (COGA). A principal component analysis was conducted on items that captured many of the dimensions of drinking and related behaviors, including aspects of alcohol use, antisocial behavior and affective disturbance when drinking, and personality. Factor scores were computed for all individuals. Nonparametric linkage analyses were conducted on these factor scores, in the initial COGA sample consisting of 987 individuals from 105 extended families, and in a replication sample consisting of 1295 individuals from 157 extended families., Results: Three factors were identified, accounting for 68% of the total variance. The most promising regions of linkage appeared for factor 2, on which higher scores indicate a later age of onset of regular drinking and higher harm avoidance. Chromosome 1 yielded consistent evidence of linkage in both samples, with a maximum lod score of 3.3 when the samples were combined for analysis. Consistent suggestion of linkage also was found to chromosome 15., Conclusions: Developing novel phenotypes that more accurately model the effect of influential genes may help efforts to detect genes involved in complex disorders. Applying principal component analysis in the COGA sample provided support for some regions of linkage previously reported in COGA, and identified other new, promising regions of linkage.

Background: There is substantial evidence for a significant genetic component to the risk for alcoholism. A previous study reported linkage to chromosomes 1, 2, and 7 in a large data set that consisted of 105 families, each with at least three alcoholic members., Methods: Additional genotyping in the 105 families has been completed in the chromosomal regions identified in the initial analyses, and a replication sample of 157 alcoholic families ascertained under identical criteria has been genotyped. Two hierarchical definitions of alcoholism were employed in the linkage analyses: (1) Individuals who met both Feighner and DSM-III-R criteria for alcohol dependence represented a broad definition of disease; and (2) individuals who met ICD-10 criteria for alcoholism were considered affected under a more severe definition of disease., Results: Genetic analyses of affected sibling pairs supported linkage to chromosome 1 (LOD = 1.6) in the replication data set as well as in a combined analysis of the two samples (LOD = 2.6). Evidence of linkage to chromosome 7 increased in the combined data (LOD = 2.9). The LOD score on chromosome 2 in the initial data set increased after genotyping of additional markers; however, combined analyses of the two data sets resulted in overall lower LOD scores (LOD = 1.8) on chromosome 2. A new finding of linkage to chromosome 3 was identified in the replication data set (LOD = 3.4)., Conclusions: Analyses of a second large sample of alcoholic families provided further evidence of genetic susceptibility loci on chromosomes 1 and 7. Genetic analyses also have identified susceptibility loci on chromosomes 2 and 3 that may act only in one of the two data sets.

Background: The clamping method of alcohol administration was combined with a battery of dependent measures of frontal lobe brain function, and a novel index of acute adaptation, in a preliminary study in order to explore the paradigm's sensitivity to a familial history of alcoholism (FHA)., Methods: Ten family history-positive (FHP) and 10 family history-negative (FHN) adult social drinkers of both genders underwent alcohol clamping. Twenty minutes after the start of an intravenous infusion of alcohol, the breath alcohol concentration was clamped at a target of 60+/-5 mg/dl for 150 min. Initial and adaptive responses to alcohol were assessed using scalar indices of change. One index assessed initial improvements or impairments in brain function after alcohol. The other index assessed acute adaptation (tolerance or sensitization) to alcohol while the brain's exposure to alcohol was held constant. The battery of dependent measures included subjective perceptions, neuropsychological tests, saccadic eye-movement tasks, and event-related potential (ERP) tasks. Effect sizes for FHA were estimated for 10 dependent variables that showed adequate baseline test-retest reliability (r>0.6)., Results: FHP subjects showed less intense initial responses to alcohol in subjective perceptions, but greater changes in the latency of volitional saccades and ERP P3 components than did the FHN controls. FHP subjects generally showed greater acute tolerance to alcohol than did controls, who showed more instances of acute sensitization at this moderate breath alcohol concentration. Effect sizes for FHA exceeded 0.4 in more than half of the indices., Conclusions: The BrAC clamping paradigm assesses initial and adaptive responses of a battery of behavioral and electrophysiological measures of frontal lobe function to ethanol that appear both reliable and sensitive to FHA.

There is substantial evidence for a significant genetic component to the risk for alcoholism. In searching for genes that contribute to this risk, the diagnostic criteria for alcohol dependence may not be the optimal phenotype; rather, creation of a more homogeneous phenotype will lead to a more homogeneous genetic etiology. Items from the Semi-Structured Assessment for the Genetics of Alcoholism collected from 830 individuals in 105 alcoholic families were used in a latent class analysis to identify a more homogeneous alcoholism-related phenotype. A four-class solution was chosen: class 1, unaffected group; class 2, mildly problematic group; class 3, moderately affected group; and class 4, severely affected group. Classes 3 and 4 had higher symptom endorsement probabilities than classes 1 and 2 for items reflecting severe alcohol dependence, and were combined to provide enough sibling pairs for genetic linkage analysis. A total of 291 markers distributed throughout the genome, with an average intermarker distance of 14 cM, were genotyped. Linkage analysis was performed to detect loci underlying classes 3 and 4, the moderately and severely affected alcoholics, of whom 88% met the Collaborative Study of the Genetics of Alcoholism, and >99% met ICD-10 criteria for alcohol dependence. Evidence for a locus on chromosome 16, near the marker D16S675, was found with a maximum multipoint lod score of 4.0. Analysis of additional markers on chromosome 16 yielded a lod score of 3.2, narrowed the critical region, and placed the gene between D16S475 and D16S675 in a 15 cM interval.

A population association between a regulatory variation in the promoter of the serotonin transporter gene (HTT) and severe alcohol dependence was recently reported. We analyzed this potential association in a large number of systematically ascertained families in the United States; these families had at least three first-degree relatives who were alcohol-dependent. Analyses focused on individuals defined as alcohol-dependent by criteria from ICD-10 and on subsets of these individuals reporting withdrawal-related symptoms. Application of the transmission disequilibrium test did not provide support for either linkage or association between this functional polymorphism and alcohol dependence; there was no significant bias in the transmission of either allele to the alcohol-dependent offspring. We also report that African Americans differ from Caucasians in allele frequencies for this polymorphism.

Objective: Platelet monoamine oxidase (MAO) B activity levels were evaluated to determine whether low platelet MAO activity is a marker for alcoholism, correlates of alcoholism (e.g., cigarette smoking), or a subtype of alcoholism., Methods: Adult women (n = 788) and men (n = 685) participating in the Collaborative Study on the Genetics of Alcoholism study were evaluated with a semistructured interview, and blood samples were obtained for determination of platelet MAO activity using tryptamine (0.1 mM) as substrate. DSM-III-R alcohol-dependent individuals were subgrouped using four currently available methods (e.g., two variations of the type 1/type 2 scheme, primary versus secondary typology, type A/type B dichotomy)., Results: In the overall sample, subjects' gender, cigarette smoking status, and the Collaborative Study on the Genetics of Alcoholism site at which their platelets were prepared explained 22% of the variance in platelet MAO activity levels, and multivariate analysis showed that carrying a broad diagnosis of alcohol dependence did not uniquely explain any additional variance in platelet MAO activity levels. Furthermore, within each of the alcoholic subgrouping methods tested, there were no significant differences in platelet MAO activity for type 1 versus type 2, type A versus type B, or primary versus secondary alcoholics., Conclusions: Cigarette smoking and male gender are associated with decreased platelet MAO activity levels. After considering these factors, a diagnosis of alcohol dependence does not predict any additional variance in MAO-B activity. Phenotypes of alcoholics (e.g., type 1 versus type 2, type A versus type B, primary versus secondary) do not differ in platelet MAO activity. The results suggest that decreased platelet MAO activity is not a trait marker of alcoholism or one of its subtypes; but, rather, is a state marker of cigarette smoking.

The possible association of the DRD2 locus, and in particular the Taql-A1 allele, with alcoholism remains controversial, in part because of differences in allele frequencies among populations. To avoid problems associated with differences in allele frequencies in different populations, we tested whether the DRD2 locus is associated with alcohol dependence in a large family-based sample. Neither the transmission/disequilibrium test nor the Affected Family-Based Controls test provide any evidence of linkage or association between the DRD2 locus and alcohol dependence.

Evidence from family, twin, and adoption studies suggest a heritable basis for alcoholism. However, alcoholism is likely to be genetically heterogeneous, and any genetic connection is likely to be in the form of genes conferring an increased risk or susceptibility. In this study, we present the evidence for a genetic component for alcoholism, and examine the precedent for genetic testing and screening for genetic susceptibility using Huntington's disease and Alzheimer's disease as examples. Finally, we discuss the preparations that need to be made before taking any findings about the genetics of alcoholism from the research laboratory into the clinic.

We attempt to identify distinctive subtypes of alcoholics using latent class analysis with data from 2551 relatives of alcoholic probands, all participants in the Collaborative Study of the Genetics of Alcoholism. Latent class analysis is a multivariate technique using cross-classified data to identify unobserved ("latent") classes that explain the relationships among observed variables. Data on 37 life-time symptoms of alcohol dependence from 1360 female and 1191 male relatives were analyzed, with a 4 class solution selected as the best fitting among the 2 through 6 class solutions that were examined. We observed the following classes: class 1, nonproblem drinkers (39.6% male, 50% female); class 2, mild alcoholics (persistent desire to stop, tolerance, and blackouts) (31.8% male, 28.7% female); class 3, moderate alcoholics (social, health, and emotional problems) (18.9% male, 14.6% female); and class 4, severely affected alcoholics (withdrawal, inability to stop drinking, craving, health, and emotional problems) (9.7% male, 6.7% female). There was little evidence for the construct of alcohol abuse; endorsement probabilities for abuse symptoms (e.g., arrest and DWIs) were very low for all classes, whereas hazardous use was common among men in class 1. In addition to those in class 3 and class 4, a majority of men in class 2 qualified for DSM-III-R alcohol dependence, suggesting a biomodal distribution of drinkers and alcoholics, with little nondependent problem drinking among men in this high-risk sample. We conclude that, in this sample, alcoholism is not differentiated by symptom profiles but rather lies on a continuum of severity, with the possible exception of withdrawal, which characterized only class 4 individuals.

Using data from The Collaborative Study on the Genetics of Alcoholism, we compare direct interview diagnoses of alcohol dependence to those obtained by history from family members. Using a requirement of three or more positive implications by history, the specificity, sensitivity, and positive predictive values are 98%, 39%, and 45%, respectively. A logistic analysis found the gender of the relative and alcoholism in the informant to be significant, but not the gender of the informant. The partial odds ratio of a diagnosis at interview associated with a positive family history diagnosis was 13.6. The relationship between the informant and relative was significant, with negative reports from an offspring or mate more influential than a negative report from a parent or second-degree relative. We derived a recursive equation to combine a variable number of family history reports, wherein the probabilities associated with a single report are computed from the logistic analysis. This permits the use of family history information both as a proxy for an uninterviewed relative, as well as a second source of information to be used in the analysis of genetic family data.