Jelger Kalmijn

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 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.

Chromosome 15q25.1 genetic markers associated with level of response to alcohol in humans

As with other genetically complex common psychiatric and medical conditions, multiple genetic and environmental components contribute to alcohol use disorders (AUDs), which can confound attempts to identify genetic components. Intermediate phenotypes are often more closely correlated with underlying biology and have often proven invaluable in genetic studies. Level of response (LR) to alcohol is an intermediate phenotype for AUDs, and individuals with a low LR are at increased risk. A high rate of concurrent alcohol and nicotine use and dependence suggests that these conditions may share biochemical and genetic mechanisms. Genetic association studies indicate that a genetic locus, which includes the CHRNA5-CHRNA3-CHRNB4 gene cluster, plays a role in nicotine consumption and dependence. Genetic association with alcohol dependence was also recently shown. We show here that two of the markers from the nicotine studies also show an association (multiple testing corrected P < 0.025) with several LR phenotypes in a sample of 367 siblings. Additional markers in the region were analyzed and shown to be located in a 250-kb expanse of high linkage disequilibrium containing three additional genes. These findings indicate that LR intermediate phenotypes have utility in genetic approaches to AUDs and will prove valuable in the identification of other genetic loci conferring susceptibility to AUDs.

The investigation into CYP2E1 in relation to the level of response to alcohol through a combination of linkage and association analysis.

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

Neurological dysfunction in asymptomatic HIV-1 infected men: evidence from evoked potentials

Neurological function in 159 subjects infected by the human immunodeficiency virus (HIV) who had no neurological symptoms or signs (129 asymptomatic, 30 with ARC/AIDS) was compared to that of 62 controls by means of pattern-reversal evoked potentials (PREPs), brain-stem auditory evoked potentials (BAEPs), median nerve somatosensory evoked potentials (MSEPs), tibial nerve somatosensory evoked potentials (TSEPs) and nerve conduction studies (NCSs). Central nervous system somatosensory conduction from lumbar cord to cortex was prolonged in both asymptomatic seropositive and ARC/AIDS groups, while peripheral somatosensory conduction, NCSs and PREP delays occurred only in the ARC/AIDS group. BAEPs did not show significant differences among groups. TSEPs were abnormal in 8% of asymptomatic carriers and 43% of patients with ARC/AIDS, MSEPs in 7% and 20%, PREPs in 4% and 0%, and BAEPs in 1% and 0% respectively. One or more evoked potentials were abnormal in 18 of 129 (14%) asymptomatic carriers and 13 of 30 (43%) subjects with ARC/AIDS as compared with 1 of 62 (2%) seronegative controls. We conclude that asymptomatic HIV carriers have subclinical neurological impairment of central somatosensory function and that the neurological impairment increases with disease progression to involve peripheral nerves and visual system.

Clinical implications of tolerance to alcohol in nondependent young drinkers

Background: Ten percent of teenagers and young adults with no alcohol diagnosis and a third of those with alcohol abuse report tolerance to alcohol. However, relatively few data are available on the clinical implications of tolerance in nondependent men and women. Methods: Data were gathered from 649 18-to-22-year-old drinking offspring from the Collaborative Study on the Genetics of Alcoholism (COGA) families. The prevalence and clinical correlates of tolerance were evaluated across subjects with no DSM-IV alcohol abuse and no tolerance, similar individuals with tolerance, subjects with alcohol abuse but no tolerance, and individuals with both alcohol abuse and tolerance. Results: Tolerance was associated with an almost doubling of the number of drinks needed to feel alcohols effects, and correlated with additional alcohol-related problems. In regression analyses, the most consistent and robust correlates of tolerance were the maximum number of drinks and alcohol problems, and tolerance remained informative after covarying for drinking quantity. Conclusions: Tolerance to alcohol may be a useful concept regarding nondependent drinkers that is not just a proxy for alcohol quantity but also reflects the presence of additional problems.

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.

The Patterns of Drug and Alcohol Use and Associated Problems Over 30 Years in 397 Men

BACKGROUND Alcohol and drug use disorders (AUDs and SUDs) and their combination are relatively common and often occur together. However, the relationships of potential early life correlates of alcohol and drug disorders to the combined diagnoses have rarely been evaluated in long-term prospective studies or in populations at high risk of one of these diagnoses but not the other. METHODS Data were analyzed from 397 males (half with an alcohol-dependent father) who had no AUDs or SUDs at age 20 and who were followed approximately every 5 years for 3 decades. Early life correlates and the course of AUDs, SUDs, and combined disorders were evaluated for 4 groups of subjects based on subsequent alcohol and/or drug diagnoses. RESULTS While the overall rates of the development of AUDs and SUDs were 41 and 21%, respectively, the rates of the second substance-related diagnosis were almost 2-fold higher for individuals who had the first condition. Among potential risk factors, scores for externalizing traits were elevated for men with AUDs, SUDs, and their combination, but a low level of response (low LR) to alcohol was associated only with the risk of AUDs, even when observed in the context of SUDs. The same earlier life characteristics that related to AUDs and to SUDs also related to the combination of these diagnoses in the same person. Finally, in this prospective study, subjects with both AUDs and SUDs had a more severe course than subjects with either condition alone. CONCLUSIONS This prospective evaluation of a group at high risk of AUDs confirmed the selective impact of the low LR on the risk of AUDs, the relationship of externalizing characteristics to both AUDs and SUDs and confirmed the more severe clinical course for both conditions when seen together.