Associations of variations in alcohol dehydrogenase genes with the level of response to alcohol in non-Asians

BACKGROUND: Risk and protective factors for alcohol use disorders (AUDs) are complex and reflect both environmental and genetic factors. Genetic components account for about 50% of the variation and influence several phenotypes, including the level of response (LR) to alcohol as well as alcohol-metabolizing enzyme polymorphisms. Variations in the ADH1B and ADH1C genes may influence the LR to alcohol by increasing levels of acetaldehyde during alcohol metabolism, although most data on this question come from Asian populations. METHODS: This study evaluated associations of ADH1B and ADH1C genotypes in a non-Asian sample. Participants (N = 117, 69.2% female) were 18- to 29-year-old men and women, primarily Caucasian (70.1%) and black (26.5%), recruited in San Diego, California. The Semi-Structured Assessment for the Genetics of Alcoholism Interview was used to assess demographic, substance use, and psychiatric history information, and the Family History Assessment Module was used to determine first-degree family history of alcohol dependence. An alcohol challenge paradigm was used to gather data on the LR to alcohol over 210 minutes. RESULTS: Participants with the ADH1B*1/*2 genotype had a higher LR to alcohol early in the alcohol challenge (i.e., 30, 60, and 90 minutes after drinking) as measured by both alcohol-related changes in subjective feelings of intoxication and body sway, even when controlling for sex and Russian/Eastern European ancestry. A similar trend was seen for ADH1C*1/*1 genotype, although the results were not significant. CONCLUSIONS: These findings suggest that studies searching for genes relating to the LR to alcohol as a vulnerability factor for AUDs should consider controlling for ADH1B genotype, as the ADH1B*2 allele could obscure the impact of other genetic polymorphisms.     

Human Variation in Alcohol Response Is Influenced by Variation in Neuronal Signaling Genes

Background: Alcohol use disorders (AUD) exhibit the properties shared by common conditions and diseases classified as genetically complex. The etiology of AUDs is heterogeneous involving mostly unknown interactions of environmental and heritable factors. A person’s level of response (LR) to alcohol is inversely correlated with a family history and the development of AUDs. As an AUD endophenotype, alcohol LR is hypothesized to be less genetically complex and closer to the primary etiology of AUDs. Methods: A genome wide association study (GWAS) was performed on subjects characterized for alcohol LR phenotypes. Gene Set Enrichment Analysis (GSEA) of the GWAS data was performed to determine whether, as a group, genes that participate in a common biological function (a gene set) demonstrate greater genetic association than would be randomly expected. Results: The GSEA analysis implicated variation in neuronal signaling genes, especially glutamate signaling, as being involved in alcohol LR variability in the human population. Conclusions: These data, coupled with cell and animal model data implicating neuronal signaling in alcohol response, support the conclusion that neuronal signaling is mechanistically involved in alcohol’s cellular and behavioral effects. Further, these data suggest that genetic variation in these signaling pathways contribute to human variation in alcohol response. Finally, this concordance of the cell, animal, and human findings supports neuronal signaling, particularly glutamate signaling, as a prime target for translational studies to understand and eventually modulate alcohol’s effects.     

The search for genes contributing to the low level of response to alcohol: patterns of findings across studies

BACKGROUND: Alcoholism is a complex genetically influenced disorder in which multiple phenotypes [e.g., disinhibition, alcohol-metabolizing patterns, and the low level of response (LR) to alcohol] contribute to the risk. A low LR to alcohol is one of the more thoroughly studied risk phenotypes; data indicate that LR relates to the risk status, predicts future alcoholism, and has a heritability as high as 60%. This article reviews data from animal and human studies regarding the LR to alcohol, searching for a convergence of results that might lead to the identification of relevant genes. METHODS: A literature search was performed regarding animal and human genetic studies focusing on genes that might affect the LR to alcohol as a risk factor for alcoholism. The goal was to synthesize these results and highlight potential patterns. RESULTS: Focusing on both genetic linkage and association studies, a number of chromosomal regions and genes potentially relevant to findings across two or more sources were identified. The genes of potential interest fell into several categories, including second-messenger systems (e.g., G proteins, adenylyl cyclase, and protein kinases); neurotransmitters or drug-related receptors (e.g., gamma-aminobutyric acid-A, glutamate, serotonin, and cannabinoid and opioid receptors); genes that affect alcohol metabolism; and genes that might relate to an overlap in the risk for alcoholism and some psychiatric conditions (e.g., catechol-O-methyltransferase regarding schizophrenia and bipolar disorder). CONCLUSIONS: The review identifies several genes that may contribute to a low LR to alcohol and, thus, to an increased risk for alcohol use disorders. The chromosomal regions and genes highlighted here may form the basis for more focused genetic studies of alcohol use disorders, with the goals of developing more specific and effective prevention and treatment approaches.     

The Relationships of the Level of Response to Alcohol and Additional Characteristics to Alcohol Use Disorders Across Adulthood: A Discrete-Time Survival Analysis

Background:  A low level of response (LR) to alcohol has been shown to relate to a higher risk for alcohol use disorders (AUDs). However, no previous research has examined the association between LR and the development of AUDs in the context of additional robust risk factors for AUDs. This study evaluated whether LR and other related characteristics predicted the occurrence of AUDs across adulthood using discrete-time survival analysis (DTSA).
Methods:  A total of 297 probands from the San Diego Prospective Study reported on the LR to alcohol, a family history (FH) of AUDs, the typical drinking quantity, the age of drinking onset, the body mass index and the age at the baseline (T1) assessment. Alcohol use disorders (AUDs) were evaluated at the 10-year (T10), T15, T20, and T25 follow-ups.
Results:  A low LR to alcohol predicted AUD occurrence over the course of adulthood even after controlling for the effects of other robust risk factors. Interaction effects revealed that the impact of FH on AUDs was only observed for subjects with high T1 drinking levels, and probands with high T1 drinking were at high risk for AUDs regardless of their age of onset.
Conclusions:  The findings illustrate that LR is a unique risk factor for AUDs across adulthood, and not simply a reflection of a broader range of risk factors. The continued investigation of how LR is related to AUD onset later in life will help inform treatment providers about this high-risk population, and future longitudinal evaluations will utilize DTSA to assess rates of AUD remission as well as the onset of drinking outcomes in adolescent samples.     

GABRA2 and Alcohol Use Disorders: No Evidence of an Association in an Italian Case–Control Study

Background: Alcoholism is a major health and social issue, a highly frequent disease and a cause of premature death. It is also the most expensive addictive disorder being related to high morbidity and mortality, violence, accidents, and social and legal problems. It is a quantitative disorder, where the combined incidence of environmental and multiple genetic factors varies from 1 subject to another. Recent association studies have identified several genes as candidates for alcoholism, including GABA_A receptor genes, due to their role in mediating several behavioral effects of alcohol, such as motor incoordination, anxiolysis, sedation, and withdrawal. The proposed association between the 3′ half of the gene encoding the alpha‐2 subunit of GABA receptor (3′‐GABRA2) and alcohol use disorders (AUDs) has received several independent confirmations. Methods: In this study, 10 single nucleotide polymorphisms (SNPs) of the 3′‐GABRA2 gene, previously reported to be implicated in alcohol dependence, were used to evaluate the linkage between selected SNPs and AUDs in an Italian sample and to compare findings with those of previous studies. Results: No evidence of an association was found at the allele, genotype, haplotype, or diplotype levels between the 3′‐GABRA2 polymorphisms investigated and alcoholism in 149 Italian alcoholics (98 alcohol dependents and 51 alcohol abusers) and 278 controls. Conclusions: Despite previous reports, we did not find an association between AUDs and 3′‐GABRA2 polymorphisms. This is probably due to the minimal comorbidity of our Italian sample suggesting that this gene is implicated in polysubstance dependence rather than in alcoholism alone.     

Testing the level of response to alcohol: social information processing model of alcoholism risk--a 20-year prospective study

BACKGROUND: The low level of response (LR) to alcohol is a genetically influenced characteristic associated with an enhanced risk for alcohol use disorders (AUDs). An optimal understanding of how this intermediate phenotype relates to the AUD risk requires evaluation of the milieu in which LR operates, and this study tested an LR/social information processing model in adult men. METHODS: Almost 300 Caucasian males (97% of those eligible, to date) from the San Diego Prospective Study participated in an alcohol challenge at approximately age 20 and were evaluated with a structural equation model regarding their expectations of the effects of alcohol, drinking among peers, use of alcohol to cope with stress, and alcohol-related problems during follow-up. RESULTS: The direct paths in the structural equation model in these 40-year-old men explained 58% of the variance of the alcoholic outcome at age 40 and 35% at age 35 while demonstrating good fitness characteristics. The LR to alcohol was related to the family history of AUDs and to the alcoholic outcome; the latter primarily operated through the use of alcohol to cope with stress. Although drinking in peers and expectations of the effects of alcohol both contributed to the model in these 40-year-old men, they were not directly related to LR. CONCLUSIONS: The results continue to support the importance of the low LR to alcohol as a predictor of AUDs, even when evaluated in the context of additional relevant characteristics. Future evaluations of adolescent and young adult subjects will also explore the potential importance of expectations of the effects of alcohol and drinking among peers as mediators or moderators of alcoholism risk among subjects with a low LR.     

Findings across subgroups regarding the level of response to alcohol as a risk factor for alcohol use disorders: a college population of women and Latinos

BACKGROUND: The rates of alcohol dependence, a genetically influenced disorder, are increased among Latino men in the United States and are lower among women across ethnic groups. These analyses explored whether the differential rate of alcohol use disorders (AUDs) might reflect one genetically influenced phenotype related to alcoholism risk: the low level of response (LR) to alcohol. METHODS: A questionnaire was mailed to students at two universities to identify drinking but not alcohol-dependent 18- to 29-year-old men and women who had a parent with alcohol dependence. Subjects were subsequently screened with a validated semistructured interview to corroborate the personal and family histories, and they participated in a challenge with alcohol 0.75 ml/kg for women and 0.90 ml/kg for men. LRs to alcohol were determined and compared between genders and between Latino versus Caucasian/Anglo subjects. RESULTS: The data revealed no consistent significant differences between genders regarding either subjective feelings of intoxication or alcohol-induced changes in body sway. A similar lack of differential between groups was observed when Latino and Caucasian/Anglo subjects were compared. However, there was at least a statistical trend for interactions when gender, ethnicity, and time were considered together; there was some evidence for a higher LR in Latina women. Perhaps reflecting the different weights and doses of alcohol used, men demonstrated higher breath alcohol concentrations, but no differences in these values were noted between Latino and Anglo populations. CONCLUSIONS: The results indicate that the LR to alcohol is not likely to explain differences in rates of AUDs between genders or these two ethnic groups overall. The possibility that a higher LR might be seen for the subgroup with the lowest AUD rate--Latina women--will require replication in larger samples of well matched groups before definitive conclusions can be drawn.     

Association between GABRA1 and drinking behaviors in the collaborative study on the genetics of alcoholism sample

BACKGROUND: A wealth of literature supports the role of gamma-aminobutyric acid (GABA) in neurobiological pathways contributing to alcohol dependence and related phenotypes. Animal studies have consistently tied rodent homologs of the GABAA receptor genes on human chromosome 5q to alcohol-related behaviors; however, human studies have produced mixed results. Family-based association analyses previously conducted in the Collaborative Study on the Genetics of Alcoholism (COGA) sample yielded no evidence of association with Diagnostic and Statistical Manual of Mental Disorder-fourth edition (DSM-IV) alcohol dependence and these genes. As a follow-up to that study, we examined several alcohol-related behaviors in the COGA sample as follows: (1) a broader definition of alcohol dependence, including DSM-III-R symptoms and Feighner criteria (referred to as COGA alcohol dependence); (2) withdrawal; (3) history of alcohol-induced blackouts; (4) level of response to alcohol; (5) age of onset of regular drinking; and (6) age at first drunkenness. METHODS: Family-based association tests were conducted, using multiple single-nucleotide polymorphisms (SNPs) in each of the 4 GABAA receptor genes on chromosome 5q. RESULTS: In GABRA1, we found evidence of association with several of the drinking behavior phenotypes, including COGA alcohol dependence, history of blackouts, age at first drunkenness, and level of response to alcohol. We did not find consistent evidence of association with the remaining genes and any of the phenotypes. CONCLUSIONS: We found evidence for association between GABRA1 and COGA alcohol dependence, history of blackouts, age at first drunkenness, and level of response to alcohol. These analyses suggest that efforts to characterize genetic contributions to alcohol dependence may benefit by examining alcohol-related behaviors in addition to clinical alcohol dependence diagnoses.     

An expanded evaluation of the relationship of four alleles to the level of response to alcohol and the alcoholism risk

BACKGROUND: Alcoholism is a complex, genetically influenced disorder the cause of which may be better understood through the study of genetically influenced phenotypes that mediate the risk. One such intermediate phenotype is the low level of response (LR) to alcohol. This project used a case-control approach to search for genes that may contribute to LR. METHODS: Data were available from alcohol challenges at approximately age 20 and regarding the development of alcohol use disorders over the subsequent 20 years for 85 men, including 40 reported in a previous genetic analysis. LR was evaluated using oral consumption of 0.75 ml/kg of alcohol, after which changes in subjective feelings of intoxication and body sway were measured. Alcohol abuse and dependence were diagnosed by DSM-III-R criteria through structured interviews administered to both the participant and an informant (usually the spouse) 10, 15, and 20 years after initial testing. Four polymorphisms were evaluated, including the serotonin transporter HTTLPR promoter ins/del, GABAAalpha6 Pro385Ser, NPY Leu7Pro, and catalase 262C>T. Two of these, HTTLPR and GABAAalpha6 Pro385Ser, had been previously associated with LR and alcoholism in a preliminary study. RESULTS: The HTTLPR L allele was significantly related to both the LR and alcoholism in an allele-dosage (stepwise) manner. Furthermore, the association remained when L alleles were subdivided into recently reported functional subtypes: the lowest LR was associated with genotypes correlated with the highest serotonin transporter expression. The GABAAalpha6 Ser385 allele showed a nonsignificant trend for association to a low LR, as had been previously observed, although the Ser385 allele is uncommon, and only 18 heterozygotes were in the current group. However, the six men with both LL and Pro385/Ser385 genotypes had the lowest LR, and each had developed alcoholism during follow-up. Neither NPY nor catalase was associated with either LR or alcoholic outcomes, although the sample did not have sufficient power for definitive conclusions. CONCLUSIONS: This report strengthens the support for a relationship between the HTTLPR L and GABAAalpha6 Ser385 alleles to low alcohol LR and to alcoholism in a prospectively studied cohort evaluated for LR in young adulthood and before the onset of alcohol dependence.     

Use of genetic analyses to refine phenotypes related to alcohol tolerance and dependence

Various explanations for the dependence on alcohol are attributed to the development of tolerance to some of alcohol's effects, alterations in sensitivity to its rewarding effects, and unknown pathologic consequences of repeated exposure. All these aspects of dependence have been modeled in laboratory rodents, and these studies have consistently shown a significant influence of genetics. Genetic mapping studies have identified the genomic location of the specific genes for some of these contributing phenotypes. In addition, studies have shown that some genes in mice seem to affect both alcohol self-administration and alcohol withdrawal severity: genetic predisposition to high levels of drinking covaries with genetic predisposition to low withdrawal severity, and vice versa. Finally, the role of genetic background on which genes are expressed is important, as are the specifics of the environment in which genetically defined animals are tested. Understanding dependence will require disentangling the multiple interactions of many contributing phenotypes, and genetic analyses are proving very helpful. However, rigorous understanding of both gene-gene and gene-environment interactions will be required to interpret genetic experiments clearly.     

A Critical Review of Methods and Results in the Search for Genetic Contributors to Alcohol Sensitivity

Attributes of alcohol sensitivity are present before alcohol use disorders (AUDs) develop, they predict those adverse alcohol outcomes, are familial in nature, and many are heritable. Whether measured by alcohol challenges or retrospective reports of numbers of drinks required for effects, alcohol sensitivity reflects multiple phenotypes, including low levels of alcohol response and alcohol‐related stimulation. Identification of genes that contribute to alcohol sensitivity could help identify individuals carrying risks for AUDs through their alcohol responses for whom early intervention might mitigate their vulnerability. Such genes could also improve understanding of biological underpinnings of AUDs, which could lead to new treatment approaches. However, the existing literature points to a wide range of genetic mechanisms that might contribute to alcohol responses, and few such genetic findings have been widely replicated. This critical review describes the potential impact of the diverse methods used to study sensitivity on the diversity of genetic findings that have been reported, places the genetic variants mentioned in the literature into broader categories rather than isolated results, and offers suggestions regarding how to advance the field by interpreting findings in light of the methods used to select research subjects and to measure alcohol sensitivity. To date, the most promising results have been for GABA, glutamate, opioid, dopamine, serotonin, and cholinergic system genes. The more gene variants that can be identified as contributors to sensitivity the better future gene screening platforms or polygenic scores are likely to be.     

Relationships among the level of response to alcohol and the number of alcoholic relatives in predicting alcohol-related outcomes

BACKGROUND: The low level of response (LR) to alcohol is related to a family history (FH) of alcohol use disorders (AUDs), and each predicts alcohol-related outcomes. Few studies have evaluated the interrelationships between the number of alcoholic relatives, LR, and a range of alcohol-related outcomes. This study tests the hypotheses that there will be an inverse relationship between LR and FH and that LR will be a better predictor of the maximum quantity of alcohol consumed. METHODS: Data were extracted from personal interviews with 376 males from 20 years of follow-up in the San Diego Prospective Study. Level of response had been established at about age 20 through alcohol challenges in this population, about half of whom had at least one alcoholic relative. Face-to-face follow-ups with both the subjects and additional informants were carried out 10, 15, and 20 years later. These analyses used correlations and regressions to evaluate the relationship between the 2 major predictors (FH and LR) and 5 alcohol-related outcomes over 20 years of follow-up. RESULTS: As predicted, the alcohol challenge-based LR correlated significantly with the number of alcoholic relatives (up to -0.17 for subjects with clearly high and low LR scores). Each of the 2 predictors correlated with the 5 outcomes, including the maximum quantity of alcohol consumed since original testing, maximum frequency, nondiagnostic alcohol-related problems, the number of 11 DSM-IV (Fourth Diagnostic and Statistical Manual of Mental Disorders) abuse and dependence items, and having developed alcohol abuse or dependence. In hierarchical regression analyses, LR contributed significantly to the prediction of all 5 outcomes, even when considered in the context of FH, with only LR predicting drinking quantity and frequency, but both items adding to the prediction of alcohol-related problems and diagnoses. These results were not affected by the intensity of usual drinking when LR had been measured at age 20. CONCLUSIONS: Both FH and LR contributed to a range of alcohol-related outcomes, with LR alone significantly predicting maximum quantity and frequency in regression analyses.     

Common Genetic Contributions to Alcohol and Cannabis Use and Dependence Symptomatology

Background: Despite mounting evidence that use of and dependence on alcohol and cannabis are influenced by heritable factors, the extent to which heritable influences on these phenotypes overlap across the 2 substances has only rarely been explored. In the current study, we quantified cross‐substance overlap in sources of variance and estimated the degree to which within‐substance associations between use and dependence measures are attributable to common genetic and environmental factors for alcohol and cannabis. Methods: The sample was comprised of 6,257 individuals (2,761 complete twin pairs and 735 singletons) from the Australian Twin Registry, aged 24 to 36 years. Alcohol and cannabis use histories were collected via telephone diagnostic interviews and used to derive an alcohol consumption factor, a frequency measure for cannabis use, and DSM‐IV alcohol and cannabis dependence symptom counts. Standard genetic analyses were conducted to produce a quadrivariate model that provided estimates of overlap in genetic and environmental influences across the 4 phenotypes. Results: Over 60% of variance in alcohol consumption, cannabis use, and cannabis dependence symptoms, and just under 50% of variance in alcohol dependence (AD) symptoms were attributable to genetic sources. Shared environmental factors did not contribute significantly to the 4 phenotypes. Nearly complete overlap in heritable influences was observed for within‐substance measures of use and dependence symptoms. Genetic correlations across substances were 0.68 and 0.62 for use and dependence symptoms, respectively. Conclusions: Common heritable influences were evident for alcohol and cannabis use and for AD and cannabis dependence symptomatology, but findings indicate that substance‐specific influences account for the majority of the genetic variance in the cannabis use and dependence phenotypes. By contrast, the substantial correlations between alcohol use and AD symptoms and between cannabis use and cannabis dependence symptoms suggest that measures of heaviness of use capture much of the same genetic liability to alcohol‐ and cannabis‐related problems as dependence symptomatology.     

Level of response to alcohol measured on the self-rating of the effects of alcohol questionnaire in a group of 40-year-old women

A low level of response (LR) to alcohol (i.e., the need for higher amounts to have an effect) is a genetically influenced characteristic that is both found in populations at high risk for future alcoholism and that predicts alcohol-related life problems in the future. A simple paper-and-pencil test that asks subjects to estimate the number of drinks required to produce each of four effects at different times in their lives, the Self-Rating of the Effects of Alcohol (SRE) questionnaire, was developed to facilitate studies of LR. However, data to date on this indirect measure of LR have focused primarily on young male populations. The current study reports SRE values from 121 middle class, middle-aged women who were selected because they were married to men who participated in a longitudinal study of sons of alcoholics and controls. As predicted, the SRE measure of LR, which records the perceived responses of alcohol early in the drinking career (FIRST 5), correlated significantly with recent drinks per drinking day (0.18, p < 0.05), a diagnosis of an alcohol use disorder (0.33, p < 0.001), and with a family history of alcohol dependence (0.20, p < 0.05). The LR value from the SRE reflecting the perceived number of drinks required for effects in the most recent 3 months correlated more closely with both quantity and frequency of drinking (0.36 and higher, p < 0.001), and related to recent nicotine use (0.23, p < 0.05). These data indicate the potential usefulness of the SRE as a measure of LR as a risk factor for alcoholism in relatively highly functioning middle-aged women.     

Gamma-aminobutyric acid receptor genes and nicotine dependence: evidence for association from a case-control study.

AIMS: The gamma-aminobutyric acid receptor A (GABRA) gene clusters on chromosomes 4 and 5 have been examined previously for their association with alcohol and drug dependence phenotypes. Compelling evidence suggests that GABRA2 is associated with alcohol and drug dependence. However, no study has investigated whether genes in the GABA(A) gene clusters are associated with nicotine dependence, an important phenotype with a high correlation to persistent smoking, the single most preventable cause of mortality world-wide. DESIGN: Using data on 1050 nicotine-dependent cases and 879 non-dependent smoking controls, we used logistic regression to examine the association between single nucleotide polymorphisms (SNPs) in 13 genes in the GABA(A) receptor system as well as GABBR2 (a GABA(B) gene). FINDINGS: We found evidence for association between four SNPs in GABRA4, two SNPs in GABRA2 and one SNP in GABRE with nicotine dependence. These included a synonymous polymorphism in GABRA2 (rs279858), lying in a highly conserved region, which has been shown previously to be associated with alcohol and drug dependence. A non-synonymous polymorphism (rs16859834/rs2229940) in GABRA4, also highly conserved, was associated at P-value of 0.03. Significant haplotypes associated with nicotine dependence were found for GABRA2. No evidence for epistatic interactions were noted. Our study did not find evidence for an association between GABBR2 gene and nicotine dependence. CONCLUSIONS: Given the potential role of compounds that enhance GABAergic neurotransmission in smoking cessation research, these findings have enormous potential for informing the wider field of addiction research.     

Is Dependence on One Drug Associated with Dependence on Other Drugs? The Cases of Alcohol,Caffeine and Nicotine

Several studies have correlated the use of one drug with that of another drug; however, whether dependence on one drug is associated with dependence on another drug, independent of any use/use association, is unclear. We asked 196 randomly-selected subjects the DSM-IV criteria for dependence as applied to alcohol, caffeine, and nicotine. Among ever users, the severity of alcohol vs nicotine dependence and alcohol vs caffeine dependence was related, but this relationship was weak (r = .22 & .31). Nicotine and caffeine dependence were not correlated. These results fail to confirm theories of commonality that hypothesize dependence on one drug predisposes to dependence on another drug.     

The search for genes related to a low-level response to alcohol determined by alcohol challenges

BACKGROUND: A low level of response (LR) to alcohol seems to relate to a substantial proportion of the risk for alcoholism and to have significant heritability. METHODS: This report describes the results of a genome-wide segregation analysis for the first 139 pairs of full siblings by using an alcohol challenge protocol as a direct measure of LR. Subjects from 18 to 29 years old were selected if the original screen indicated they had an alcohol-dependent parent, reported a personal history of drinking but had no evidence of alcohol dependence, and had a full sibling with similar characteristics. Body sway and Subjective High Assessment Scale scores were measured at baseline and at regular intervals after the administration of a measured dose of alcohol. Participants and available parents were genotyped for 811 microsatellite markers, and resulting data were analyzed with a variance component method. RESULTS: Nine chromosome regions with logarithm of the odds ratio (LOD) between 2.2 and 3.2 were identified; several had previously been implicated regarding phenotypes relevant to alcoholism and the LR to alcohol. Several regions identified in the previous linkage study by using a retrospective self-report questionnaire were potentially confirmed by this study. The strongest evidence was on chromosomes 10, 11, and 22. CONCLUSIONS: Several chromosomal areas seem to relate to the low LR to alcohol as a risk factor for alcohol dependence.     

Neuropeptide Y receptor genes are associated with alcohol dependence, alcohol withdrawal phenotypes, and cocaine dependence

Background: Several lines of evidence in both human and animal studies suggest that variation in neuropeptide Y (NPY) or its receptor genes (NPY1R, NPY2R and NPY5R) is associated with alcohol dependence as well as alcohol withdrawal symptoms. Additional studies suggest that cocaine may affect NPY expression. Methods: A total of 39 single nucleotide polymorphisms (SNPs) were genotyped across NPY and its 3 receptor genes in a sample of 1,923 subjects from 219 multiplex alcoholic families of European American descent recruited as part of the Collaborative Studies on the Genetics of Alcoholism (COGA) study. Family‐based association analysis was performed to test the primary hypothesis that variation in these genes is associated with alcohol dependence. Secondary analyses evaluated whether there was an association of these SNPs with symptoms of alcohol withdrawal, cocaine dependence, or comorbid alcohol and cocaine dependence. Results: Although variations in NPY itself were not associated with these phenotypes, variations in 2 NPY‐receptor genes were. SNPs in NPY2R provided significant evidence of association with alcohol dependence, alcohol withdrawal symptoms, comorbid alcohol and cocaine dependence, and cocaine dependence (all p < 0.03). Haplotype analyses strengthened the evidence for these phenotypes (global 0.0004 < p < 0.005). SNPs in NPY5R demonstrated significant association with alcohol withdrawal characterized by seizures (p < 0.05). Conclusion: These results indicate that sequence variations in NPY receptor genes are associated with alcohol dependence, particularly a severe subtype of alcohol dependence characterized by withdrawal symptoms, comorbid alcohol and cocaine dependence, and cocaine dependence.     

Effect of Fetal Alcohol Exposure on Adult Symptoms of Nicotine, Alcohol, and Drug Dependence

Objectives : The objective of this study is to examine the effect of fetal alcohol exposure on later substance dependence using an adoption study method. Methods : One hundred ninety-seven adoptees were interviewed for substance abuse disorders, including nicotine, alcohol, and drug dependence. Twenty-one adoptees had mothers who drank during pregnancy. Adoptees with fetal alcohol exposure were compared with those without fetal alcohol exposure for symptoms of adult nicotine, alcohol, and drug dependence. Results : Adoptee symptom counts for alcohol, drug, and nicotine dependence were higher for those exposed to alcohol in utero. The effect of fetal alcohol exposure remained after controlling for gender, biological parent alcohol dependence diagnosis, birth weight, gestational age and other environmental variables. Conclusions : Fetal alcohol exposure may produce increased risk for later nicotine, alcohol, and drug dependence. Possible effects of fetal alcohol exposure on development of adult substance use patterns needs attention in genetic studies of substance abuse.     

WHO/ISBRA Study on State and Trait Markers of Alcohol Use and Dependence: analysis of demographic,behavioral, physiologic,and drinking variables that contribute to dependence and seeking treatment. International Society on Biomedical Research on Alcoholism

Background Discussions between the World Health Organization (WHO) and the International Society on Biomedical Research on Alcoholism (ISBRA) identified the need for a multiple‐center international study on state and trait markers of alcohol abuse and alcohol dependence. The reasoning behind the generation of such a project included the need to understand the alcohol use characteristics of diverse populations and the performance of biological markers of alcohol use in a variety of settings throughout the world. A second major reason for initiating this study was to collect DNA for well‐structured and stratified association studies between genetic markers and/or “candidate” genes and behavioral/physiological phenotypes of importance to predisposition to alcohol dependence. Methods An extensive interview instrument was developed with leadership from the U.S. National Institute on Alcohol Abuse and Alcoholism (NIAAA). The instrument was translated from English to Finnish, French, German, Japanese, and Portuguese (Brazilian). One thousand eight hundred sixty‐three subjects were recruited at five clinical centers (Montreal, Canada; Helsinki, Finland; Sapporo, Japan; São Paulo, Brazil; and Sydney, Australia). The subjects responded to the structured interview and provided blood and urine samples for biochemical analysis. This article focuses on the demographic characteristics of the study subjects, their drinking habits, alcohol‐dependence characteristics, comorbid psychiatric and other drug variables, and predictors for seeking treatment for alcohol dependence. Multiple logistic regression models were constructed and used to explore variables that contribute to various levels of alcohol consumption, to a diagnosis of alcohol dependence, and to seeking treatment for alcohol dependence. ANOVA with post hoc comparisons, χ², and Pearson moment calculations were used as necessary to assess additional relationships between variables. Results A number of factors previously noted in disparate studies were confirmed in our analysis. Men consumed more alcohol than women, Asians consumed less alcohol than whites or Blacks, alcohol‐dependent subjects consumed more alcohol than nondependent subjects, alcohol consumption increased with age, and an increased level of education (university or postgraduate education) reduced the percentage of such individuals in the category designated as heavy drinkers (>210 g alcohol/week) and in the group who were currently in treatment for dependence. However, our analysis allowed for much more detailed comparisons; for example, although men drank more than women on a g/day basis, the differences were less pronounced on g/kg/day basis, and alcohol‐dependent women drank equal amounts of alcohol as alcohol‐dependent men on a g/kg/day basis. Antisocial personality characteristics or reports of trouble sleeping when an individual stops drinking were associated with higher alcohol intake. The most important of the tested factors that contributed to a DSM‐IV diagnosis of dependence, however, was the report of anxiety if an individual stopped drinking. In terms of the various criteria within the DSM‐IV criteria for alcohol dependence, no one criterion seemed to be prominent for individuals who sought alcohol dependence treatment, but the higher the number of criteria met by the individual, the higher was the probability that he or she would be in treatment. Conclusions This initial report is the beginning of the “data mining” of this rich data set. The cross‐national/cross‐cultural aspects of this study allowed for multiple comparisons of variables across several ethnic/racial groups and allowed for assessment of biochemical markers for alcohol intake and predisposition to alcohol dependence in diverse settings.