Genetic and neurophysiological correlates of the age of onset of alcohol use disorders in adolescents and young adults.

Discrete time survival analysis was used to assess the age-specific association of event-related oscillations (EROs) and CHRM2 gene variants on the onset of regular alcohol use and alcohol dependence. The subjects were 2,938 adolescents and young adults ages 12-25. Results showed that the CHRM2 gene variants and ERO risk factors had hazards which varied considerably with age. The bulk of the significant age-specific associations occurred in those whose age of onset was under 16. These associations were concentrated in those subjects who at some time took an illicit drug. These results are consistent with studies which associate greater rates of alcohol dependence among those who begin drinking at an early age. The age specificity of the genetic and neurophysiological factors is consistent with recent studies of adolescent brain development, which locate an interval of heightened vulnerability to substance use disorders in the early to mid teens.

Evidence for genes on chromosome 2 contributing to alcohol dependence with conduct disorder and suicide attempts.

Twin studies provide strong evidence that there is a shared genetic liability that predisposes to a number of different psychiatric outcomes related to behavioral disinhibition. Further, alcohol dependence comorbid with other disinhibitory disorders is particularly heritable. Chromosome 2p14-2q14.3 has been linked to multiple psychiatric conditions related to behavioral undercontrol. In the Collaborative Study on the Genetics of Alcoholism (COGA), we previously reported linkage to this region with alcohol dependence (AD), suicide attempts (SUI), and conduct disorder (CD). In this study, we follow-up on these previous reports of linkage by combining the phenotypes in analyses that jointly consider the presence of multiple conditions. Linkage analyses of the combined phenotype of AD with CD or SUI results in a maximum LOD score of 5.4 in this region. In addition to this primary linkage peak, independent samples have reported linkage to other alcohol-related phenotypes across chromosome 2. Accordingly, we followed-up these linkage signals by testing for association with SNPs across chromosome 2 in a case-control sample, in which a subset of the cases consisted of alcohol-dependent probands from the linkage sample. We find evidence of association with the combined AD with CD or SUI phenotype, with 23 genes surviving permutation testing. The number of associated genes across the chromosome may explain the persistent linkage findings reported on chromosome 2 across a number of independent studies of alcohol and disinhibitory phenotypes. Further, none of the genes were located directly under the primary COGA linkage peak, which has implications for association tests following-up linkage peaks.

Genome-wide association study of alcohol dependence implicates a region on chromosome 11.

BACKGROUND: Alcohol dependence is a complex disease, and although linkage and candidate gene studies have identified several genes associated with the risk for alcoholism, these explain only a portion of the risk. METHODS: We carried out a genome-wide association study (GWAS) on a case-control sample drawn from the families in the Collaborative Study on the Genetics of Alcoholism. The cases all met diagnostic criteria for alcohol dependence according to the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition; controls all consumed alcohol but were not dependent on alcohol or illicit drugs. To prioritize among the strongest candidates, we genotyped most of the top 199 single nucleotide polymorphisms (SNPs) (p < or = 2.1 x 10(-4)) in a sample of alcohol-dependent families and performed pedigree-based association analysis. We also examined whether the genes harboring the top SNPs were expressed in human brain or were differentially expressed in the presence of ethanol in lymphoblastoid cells. RESULTS: Although no single SNP met genome-wide criteria for significance, there were several clusters of SNPs that provided mutual support. Combining evidence from the case-control study, the follow-up in families, and gene expression provided strongest support for the association of a cluster of genes on chromosome 11 (SLC22A18, PHLDA2, NAP1L4, SNORA54, CARS, and OSBPL5) with alcohol dependence. Several SNPs nominated as candidates in earlier GWAS studies replicated in ours, including CPE, DNASE2B, SLC10A2, ARL6IP5, ID4, GATA4, SYNE1, and ADCY3. CONCLUSIONS: We have identified several promising associations that warrant further examination in independent samples.

GABRR1 and GABRR2, encoding the GABA-A receptor subunits rho1 and rho2, are associated with alcohol dependence.

The genes encoding several GABA-A receptor subunits, including GABRA2, have been associated with alcoholism, suggesting that variations in gaba signaling contribute to risk. Therefore, as part of a comprehensive evaluation of the GABA receptor genes, we evaluated the potential association of GABRR1 and GABRR2, which encode the rho1 and rho2 subunits of the pentameric GABA-A/GABA-C receptors. GABRR1 and GABRR2 lie in a head to tail orientation spanning 137 kb on chromosome 6q14-16. We genotyped 73 single nucleotide polymorphisms (SNPs), covering both genes and extending 31 kb upstream of GABRR2 and 95 kb downstream of GABRR1, in a sample of 1923 European Americans from 219 multiplex alcohol-dependent families. Family-based association analyses demonstrated that SNPs in both GABRR1 and GABRR2 were significantly associated with alcohol dependence. Among the associated SNPs was rs282129, a coding SNP (Met430Thr) in GABRR2. Secondary analysis using a median split for age of onset suggests that the association is strongest when the analysis is focused upon those with earlier onset of alcohol dependence. Haplotypes in each gene were significantly overtransmitted to family members who did not meet criteria for alcohol dependence (P < 0.04), and a haplotype in GABRR2 was significantly overtransmitted to family members who met a broader definition of alcoholism (P = 0.002) as well as DSM-IV dependence (P = 0.04).

Association of NFKB1, which encodes a subunit of the transcription factor NF-kappaB, with alcohol dependence.

A broad region on chromosome 4q has been linked to alcohol dependence (alcoholism). We hypothesized that such broad linkage regions represent the combined action of multiple genes. Seeking to identify genes within that region that are associated with alcoholism, we have tested the association of NFKB1, located at 4q24, with alcoholism. NFKB1 encodes a 105 kDa transcription inhibitor that is cleaved to the 50 kDa DNA-binding subunit of the ubiquitous transcription factor NF-kappaB. NF-kappaB regulates many genes relevant to brain function, and its actions can be potentiated by ethanol; thus, NFKB1 is an excellent candidate gene for alcoholism. Nineteen SNPs in and near NFKB1 were analyzed in a sample of 219 multiplex alcoholic families of European American descent. Family-based association analyses detected significant evidence of association with eight SNPs and marginal evidence for five more. The association was driven by the affected individuals with earlier onset of alcoholism (55% of the sample with onset < or =21 years). Further analysis of the age of onset as a quantitative variable provided evidence for the association of 12 SNPs in this gene. Thus, variations in NFKB1 appear to affect the risk for alcoholism, particularly contributing to an earlier onset of the disease.

The relationship between alcohol problems and dependence, conduct problems and diagnosis, and number of sex partners in a sample of young adults.

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.

Family-based association analyses of alcohol dependence phenotypes across DRD2 and neighboring gene ANKK1.

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.

Association of CHRM2 with IQ: converging evidence for a gene influencing intelligence.

The cholinergic neurotransmitter system is thought to be involved in many aspects of memory, attention, and higher cognition. In the Collaborative Study on the Genetics of Alcoholism (COGA) sample, we have previously reported linkage and association to the cholinergic muscarinic 2 receptor gene (CHRM2) on chromosome 7 with evoked EEG oscillations (Jones et al. 2004), providing evidence that this gene may be involved in human brain dynamics and cognition. In addition, a small number of genetic markers were genotyped in CHRM2 in the Minnesota Twin and Family Study (Comings et al. 2003) and a Dutch family study (Gosso et al. 2006, in press) and both research groups found evidence that this gene may be involved in intelligence. In the COGA sample, we have extensively genotyped SNPs within and flanking the CHRM2 gene. We find evidence of association with multiple SNPs across CHRM2 and Performance IQ, as measured by the Wechsler Adult Intelligence Scale-Revised (WAIS-R). These results remain significant after taking into account alcohol dependence and depression diagnoses in the sample.

Association analyses of the serotonin transporter gene with lifetime depression and alcohol dependence in the Collaborative Study on the Genetics of Alcoholism (COGA) sample.

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.

Linkage analyses of IQ in the collaborative study on the genetics of alcoholism (COGA) sample.

Intelligence, as measured by standardized psychological tests, has been shown to be highly heritable, though identifying specific genes influencing general intelligence has proven difficult. We conducted genome-wide linkage analyses to identify chromosomal regions containing genes influencing intelligence, as measured by WAIS full-scale IQ (FSIQ), performance IQ (PIQ) and verbal IQ (VIQ). Non-parametric multipoint linkage analyses were conducted with Merlin-regress software, using a sample of 1,111 genotyped and phenotyped individuals from 201 families, ascertained as part of the Collaborative Study on the Genetics of Alcoholism (COGA). The strongest evidence of linkage was obtained for FSIQ on chromosome 6 (LOD=3.28, 12 cM) near the marker D6S1006. This region was also implicated with suggestive linkage in a recently published genome screen of IQ in Australian and Dutch twin pairs, and it has been implicated in linkage studies of developmental dyslexia. Our findings provide further support that chromosome 6p contains gene(s) affecting intelligence.

Evaluation of a level of response to alcohol-based structural equation model in adolescents.

OBJECTIVE: A low level of response (LR) to alcohol relates to a family history of alcoholism and predicts future heavier drinking and alcohol-related problems. The current analyses evaluate how LR functions within the context of a Social Information Processing Model, using 238 subjects aged 13 to 19 years from the Collaborative Study on the Genetics of Alcoholism (COGA). METHOD: A structural equation model (SEM) was used to evaluate the relationship among (1) a family history (FH) of alcoholism, (2) the LR to alcohol, (3) expectations as measured by the Alcohol Expectancy Questionnaire and (4) the recent pattern of drinking among parents in the home as predictors of the maximum recent quantity of drinking, the maximum number of drinks ever consumed in 24 hours and the number of alcohol problems in the teenage subjects. RESULTS: When tested in the SEM, LR functioned as a mediator of the relationship between an FH of alcoholism and alcoholic outcome, and expectancy functioned as a partial mediator of the relationship between LR and outcome. Invariance testing revealed that the SEM performed similarly in light and heavy drinkers, the two sexes, and older versus young subjects. Both the measurement model and SEM had good characteristics of fit, and direct paths within the model explained 49% of the variance of outcome. CONCLUSIONS: Consistent with results from the San Diego Prospective Study, when tested in the more heterogeneous COGA population, LR functioned as a mediator of the relationship between the FH and alcoholic outcome. In these adolescents, LR not only had a direct relationship to alcoholic outcome but, in contrast to prior results in adults, also appeared to operate through expectations of the effects of alcohol in predicting heavier drinking and a higher rate of alcohol-related problems among teenagers.

Association of GABRG3 with alcohol dependence.

BACKGROUND: Evidence from human, animal, and in vitro cell models suggests that gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the human central nervous system, is involved in many of the neurochemical pathways that affect alcohol use, abuse, and dependence. Both linkage and association to the region on chromosome 15q that contains a cluster of GABAA receptor genes have previously been reported, but the role of these genes in alcoholism remains inconclusive. METHODS: We conducted family-based association analyses by using a large sample of multiplex alcoholic families collected as part of the Collaborative Study on the Genetics of Alcoholism, to test for an association between alcohol dependence and the GABAA receptor genes clustered on chromosome 15q. Multiple single-nucleotide polymorphisms were tested in each of the three chromosome 15q GABAA receptor genes: GABRA5, GABRB3, and GABRG3. RESULTS: Using both classic trio-based analyses and extended-family analyses, we found consistent evidence of association between alcohol dependence and GABRG3. Nearly all single-nucleotide polymorphisms across the gene yielded evidence of association, and haplotype analyses were highly significant. No consistent evidence of association was observed with either GABRA5 or GABRB3, nor was there evidence for parent-of-origin effects with any of the genes. CONCLUSIONS: These analyses suggest that GABRG3 may be involved in the risk for alcohol dependence. These findings support the theory that the predisposition to alcoholism may be inherited as a general state of central nervous system disinhibition/hyperexcitability that results from an altered responsiveness to GABA.

Theta power in the EEG of alcoholics.

BACKGROUND: In this study, the magnitude and spatial distribution of theta power in the resting EEG were examined to explore the changes in the neurophysiological status of the alcoholic brain. Some state- and trait-related issues of theta power increases in the EEG of alcoholics were also examined. METHODS: Absolute theta (3-7 Hz) power in eyes-closed EEGs of 307 alcohol-dependent subjects and 307 age- and gender-matched unaffected controls were compared by using a repeated-measures ANOVA for the entire region and three subregions (frontal, central, and parietal) separately. Supplementary to the main analysis, the effect of three clinical variables on absolute theta power was examined separately for each gender by using correlation and regression analyses. Gender differences in the theta log power difference between alcoholics and controls were explored by using regional repeated-measures ANOVA. RESULTS: Increased absolute theta power was seen in alcohol-dependent subjects at all scalp locations. The theta log power increase in male alcoholics was prominent at the central and parietal regions and in female alcoholics at the parietal region when compared with the respective matched controls. Correlation of drinking variables with log theta power exhibited no group-specific differences. CONCLUSIONS: Increased tonic theta power in the EEG may reflect a deficiency in the information-processing capacity of the central nervous system in alcoholics. The theta power increase may also be an electrophysiological index of the imbalance in the excitation-inhibition homeostasis in the cortex. It is likely that the theta power increase is a trait-related phenomenon and is expressed to differing degrees in the two genders.