Pathophysiology Of Alcohol Dependence Research Articles

Genome-wide association study of alcohol dependence implicates KIAA0040 on chromosome 1q.

Previous studies using SAGE (the Study of Addiction: Genetics and Environment) and COGA (the Collaborative Study on the Genetics of Alcoholism) genome-wide association study (GWAS) data sets reported several risk loci for alcohol dependence (AD), which have not yet been well replicated independently or confirmed by functional studies. We combined these two data sets, now publicly available, to increase the study power, in order to identify replicable, functional, and significant risk regions for AD. A total of 4116 subjects (1409 European-American (EA) cases with AD, 1518 EA controls, 681 African-American (AA) cases, and 508 AA controls) underwent association analysis. An additional 443 subjects underwent expression quantitative trait locus (eQTL) analysis. Genome-wide association analysis was performed in EAs to identify significant risk genes. All available markers in the genome-wide significant risk genes were tested in AAs for associations with AD, and in six HapMap populations and two European samples for associations with gene expression levels. We identified a unique genome-wide significant gene--KIAA0040--that was enriched with many replicable risk SNPs for AD, all of which had significant cis-acting regulatory effects. The distributions of -log(p) values for SNP-disease and SNP-expression associations for all markers in the TNN-KIAA0040 region were consistent across EAs, AAs, and five HapMap populations (0.369 ≤ r ≤ 0.824; 2.8 × 10⁻⁹ ≤ p ≤ 0.032). The most significant SNPs in these populations were in high LD, concentrating in KIAA0040. Finally, expression of KIAA0040 was significantly (1.2 × 10⁻¹¹ ≤ p ≤1 .5 × 10⁻⁶) associated with the expression of numerous genes in the neurotransmitter systems or metabolic pathways previously associated with AD. We concluded that KIAA0040 might harbor a causal variant for AD and thus might directly contribute to risk for this disorder. KIAA0040 might also contribute to the risk of AD via neurotransmitter systems or metabolic pathways that have previously been implicated in the pathophysiology of AD. Alternatively, KIAA0040 might regulate the risk via some interactions with flanking genes TNN and TNR. TNN is involved in neurite outgrowth and cell migration in hippocampal explants, and TNR is an extracellular matrix protein expressed primarily in the central nervous system.

Lack of association between SNPs in the NEUROD2 gene and alcohol dependence in a German patient sample

Results of a human post mortem study performed by our own group have suggested that the transcription factor NEUROD2, which plays a role in neuronal development, as well as in the development of anxiety and risk behavior in mice, might be a susceptibility factor for addictive disorders. Therefore the aim of the present study was to analyze a possible relation between genetic variants in the NEUROD2 gene and alcohol dependence in a sample of the Munich Gene Bank of Alcoholism (MGBA). We performed single SNP (single nucleotide polymorphism) and haplotype studies in 430 alcohol-dependent patients and 365 healthy controls with four SNPs covering the gene region of NEUROD2. Neither single SNP nor haplotype analysis could detect significant associations with alcohol dependence. Additionally we could not detect any relation of the analyzed genetic variants to Cloninger's Type 1/2 or Babor's Type A/B classification, to the age of onset or to the amount of alcohol intake. Our results do not provide evidence for an involvement of NEUROD2 polymorphisms in the pathophysiology of alcohol dependence. Further association studies are needed to confirm our findings.

No association of alcohol dependence with HOMER 1 and 2 genetic variants

Several lines of evidence indicate that alterations of the central cortico-accumbens glutamate pathway are involved in the development and maintenance of alcohol- and substance-use disorders. The HOMER protein family is encoded by 3 genes HOMER (1-3) which are components of the excitatory postsynaptic density complex and function to modulate synaptic activity by the regulation of glutamate signaling. HOMER 1 and 2 have been reported to contribute to chronic alcohol-induced long-term neurochemical changes in the endogenous reward system. Data from animal models suggest a potential role of the Homer protein family in the development of alcohol and substance use. The aim of this study is to assess potential associations between HOMER 1 and 2 genetic variants in a larger sample of alcohol-dependent individuals and unrelated controls. Five genetic variants of HOMER 1 and 3 of HOMER 2 were genotyped in a multi-site sample of 1,923 German healthy controls and 2,039 alcohol-dependent subjects. Neither single SNP nor haplotype analysis could detect significant associations with alcohol dependence (AD) and related phenotypes. While most of the HOMER 1 and 2 SNPs are in low-to-moderate linkage disequilibrium, three major haplotypes of HOMER 1 and 4 haplotypes of HOMER 2 are present in the majority of alcohol-dependent and control subjects. In conclusion, our results suggest that single SNPs, respectively, haplotypes of the HOMER 1 and 2 genes are unlikely to play a major role in the pathophysiology of AD.

Alcohol dependence is associated with reduced plasma and fundic ghrelin levels

Conflicting data concerning the involvement of ghrelin in the pathophysiology of alcohol dependence have been reported. The aim of this study is to investigate how chronic alcohol ingestion influences plasma ghrelin levels and whether potential changes observed in plasma relate to modifications in ghrelin production in the stomach where this peptide is primarily synthesized. Fifty-one consecutive alcoholics admitted for alcohol withdrawal were prospectively enrolled and compared to a control group of 32 healthy volunteers matched for age, sex, height and weight. All subjects underwent fasting plasma ghrelin determination. Twenty-seven randomly selected alcoholics and 17 controls underwent gastroscopy for fundic and duodenal biopsies. Tissues were fixed for histology or frozen in liquid nitrogen for ghrelin protein and mRNA determinations by a radioimmunoassay and quantitative polymerase chain reaction, respectively. Alcohol consumption was normalized to body weight (BW) or body mass index (BMI) given the influence of BW and volume distribution on alcohol levels. Plasma and fundic ghrelin protein levels were significantly decreased in alcoholics. Fundic but not plasma ghrelin protein levels inversely correlated with alcohol consumption normalized to BW or BMI. Ghrelin mRNA levels in fundic biopsies were similar in alcoholics and controls. No significant differences in duodenal ghrelin protein and mRNA levels were found between both groups. Alcoholism was associated with decreased plasma ghrelin levels partly due to reduced ghrelin production in the stomach. Alcohol affected ghrelin production on the post-transcriptional level in the fundus, whereas duodenal ghrelin secretion did not respond in a similar manner to alcohol intake.

Analysis of Single Nucleotide Polymorphisms and Haplotypes in the Neuropeptide Y Gene: No Evidence for Association With Alcoholism in a German Population Sample

Several lines of evidence from animal and electrophysiological studies indicate that the neuropeptide Y (NPY) gene is involved in the pathophysiology of alcohol dependence. Recent studies have provided evidence for an association between a Leu7Pro polymorphism, as well as 2 promoter single nucleotide polymorphisms (SNPs) in the NPY gene (G-602T, T-399C) and alcohol dependence. The aim of the present study was to analyze these variants in a large sample of the Munich Gene Bank of Alcoholism. We performed single SNP and haplotype studies in 465 alcohol dependent patients and 448 healthy controls with 3 SNPs in the promoter region (-883ins/del, G-602T, T-399C) and the Leu7Pro polymorphism in exon 2 of the NPY gene. Neither single SNP-, nor haplotype analysis could detect significant associations with alcohol dependence. Additionally we could not detect any relation to Cloninger's Type 1/2 or Babor's Type A/B classification, to withdrawal symptoms, to the age of onset or to the amount of alcohol intake. In conclusion, our results suggest that the analyzed SNPs, as well as the corresponding haplotypes of the NPY gene are unlikely to play a major role in the pathophysiology of alcohol dependence in the investigated sample from the German population. Further analyses are needed to confirm the present results.

Memantine for Alcohol Dependence: An Open-label Pilot Study

BackgroundGlutamatergic function, particularly that mediated by the N-methyl-D-aspartate (NMDA) receptor, has been implicated in the pathophysiology of alcohol dependence. Preclinical and human laboratory studies of memantine, an NMDA-receptor channel blocker, suggest that it may reduce alcohol cons

SNP- and Haplotype Analysis of the Tryptophan Hydroxylase 2 Gene in Alcohol-Dependent Patients and Alcohol-Related Suicide

Several lines of evidence indicate that disturbances of the central serotonergic system are involved in the pathophysiology of alcohol dependence and suicidal behavior. Recent studies have indicated that a newly identified second isoform of the tryptophan hydroxylase gene (TPH2) is preferentially involved in the rate limiting synthesis of neuronal serotonin. Genetic variations in the TPH2 gene have been associated with an increased risk for major depression and suicidal behavior. We performed single SNP (single nucleotide polymorphism), linkage disequilibrium and haplotype studies on 353 alcohol-dependent patients of whom 102 individuals had a history of at least one suicide attempt and 305 healthy controls with 20 SNPs covering the entire gene region of TPH2. Neither single SNP-, nor haplotype analysis could detect significant associations with alcohol dependence and/or suicidal behavior among alcohol-dependent patients. One major haplotype block of strong linkage disequilibrium between introns 5 and 8 of the TPH2 gene has been found in alcoholics and controls, which is in concordance with recent reports. In conclusion, our results suggest that single SNPs, respectively, haplotypes of the TPH2 gene are unlikely to play a major role in the pathophysiology of alcohol dependence or the alcoholism-related phenotype suicidal behavior. Further analysis are needed to confirm these results.

Serum cytokine concentrations in alcohol-dependent individuals without liver disease

In the current study, our aim was to evaluate and investigate the influence of heavy alcohol intake on serum interleukin (IL)-6, IL-8, IL-10, IL-12, and tumor necrosis factor-alpha (TNF-α) concentrations. The selection of cytokines was based on their presumptive role in the pathophysiology of alcohol dependence. On admission to the Drug-Free Substance Addiction Detoxification clinic (“ATHENA”), blood samples were obtained from study participants, and serum cytokine concentrations were measured by using a commercial sandwich enzyme-linked immunosorbent assay technique. Alcohol dependence, as diagnosed according to DSM–IV [ Diagnostic and Statistical Manual of Mental Disorders (4th ed.)] criteria for alcohol dependence and estimated by using the Composite International Diagnostic Interview ( CIDI), was characterized by increased serum IL-6 concentration. Interleukin-8, IL-10, IL-12, and TNF-α concentrations were comparable to those found in control subjects ( P > .05). These results indicate that in alcohol-dependent individuals there is a significant increase in the serum IL-6 concentration ( P < .05).

Finding Paradigms for the Future of Alcoholism Research: An Interdisciplinary Perspective

This is a review article and critique of current research strategies in the alcohol field. Although the alcohol field is proud of its multidisciplinary tradition and scientific findings within specific disciplines, there are very few models of cross-disciplinary research and communication. Currently, the favored model of risk is genetic; the favored model of pathophysiology is molecular neuroscience; and the favored model of clinical investigation is narrowly categorical. If there is a hierarchy within science that is based on explanatory power, then models of alcoholism emerging from neuroscience, molecular biology, and genetics should be able to accommodate (if not account for) the findings on clinical aspects of alcohol dependence, as well as data on differential risk, course, and recovery that come from the behavioral and social sciences. The first section of this article reviews the most popular models of alcohol dependence over the past 40 years. I argue that the currently fashionable categorical approach to diagnosis in DSM-IV (and ICD-10) has failed to serve as a framework for interdisciplinary research and has failed to meet the needs of human geneticists, population-based researchers, psychosocial researchers, basic scientists working in animal models, and patient-oriented researchers. I argue for a return to the dimensional approach to diagnosis in the alcohol dependence syndrome construct. In the second section of the article, I lay out an agenda for revitalized patient-oriented research in the alcohol field, as a bridge between basic biological research and innovations in clinical practice, as well as the key to a valid diagnostic system that can inform research strategies in genetics and population-based research. In the third section of the article, I highlight the interface between genetic and psychosocial models of risk and propose a possible structure for future collaboration. I conclude with a plea to funding agencies and investigators to translate discipline-based scientific findings into a science relevant to alcoholism by addressing the challenges and opportunities of an interdisciplinary research agenda on the pathophysiology of alcohol dependence and the multidimensional sources of risk.

Finding Paradigms for the Future of Alcoholism Research: An Interdisciplinary Perspective

This is a review article and critique of current research strategies in the alcohol field. Although the alcohol field is proud of its multidisciplinary tradition and scientific findings within specific disciplines, there are very few models of cross-disciplinary research and communication. Currently, the favored model of risk is genetic; the favored model of pathophysiology is molecular neuroscience; and the favored model of clinical investigation is narrowly categorical. If there is a hierarchy within science that is based on explanatory power, then models of alcoholism emerging from neuroscience, molecular biology, and genetics should be able to accommodate (if not account for) the findings on clinical aspects of alcohol dependence, as well as data on differential risk, course, and recovery that come from the behavioral and social sciences. The first section of this article reviews the most popular models of alcohol dependence over the past 40 years. I argue that the currently fashionable categorical approach to diagnosis in DSM-IV (and ICD-10) has failed to serve as a framework for interdisciplinary research and has failed to meet the needs of human geneticists, population-based researchers, psychosocial researchers, basic scientists working in animal models, and patient-oriented researchers. I argue for a return to the dimensional approach to diagnosis in the alcohol dependence syndrome construct. In the second section of the article, I lay out an agenda for revitalized patient-oriented research in the alcohol field, as a bridge between basic biological research and innovations in clinical practice, as well as the key to a valid diagnostic system that can inform research strategies in genetics and population-based research. In the third section of the article, I highlight the interface between genetic and psychosocial models of risk and propose a possible structure for future collaboration. I conclude with a plea to funding agencies and investigators to translate discipline-based scientific findings into a science relevant to alcoholism by addressing the challenges and opportunities of an interdisciplinary research agenda on the pathophysiology of alcohol dependence and the multidimensional sources of risk.