Genetics Of Alcohol Dependence Research Articles

Associations of CB1 cannabinoid receptor (CNR1) gene polymorphisms with risk for alcohol dependence: Evidence from meta-analyses of genetic and genome-wide association studies.

Objectives:Reported associations of the cannabinoid receptor 1 (CNR1) single nucleotide polymorphisms (SNPs) with alcohol dependence (AD) have been inconsistent, prompting a meta-analysis to obtain more precise estimates.Methods:A Boolean search of 4 databases (PubMed, Scopus, Google Scholar, and Mednar) sought articles that evaluated the association between CNR1 polymorphisms and risk of AD. We selected the articles with sufficient genotype frequency data to enable calculation of odds ratios (ORs) and 95% confidence intervals (CIs). Using the Population Intervention Comparators Outcome elements, AD patients (P) were compared by genotype data between AD-participants (I) and non-AD-participants (C) in order to determine the risk of AD (O) attributed to the CNR1 SNPs. Analyzing 4 SNPs (rs1049353, rs1535255, rs2023239, and rs806379) using standard genetic models, we examined associations where multiple comparisons were Holm–Bonferroni corrected. The pooled ORs were assessed for aggregate statistical power and robustness (sensitivity analysis). Subgroups were Caucasians and African-Americans.Results:From 32 comparisons, 14 were significant indicating increased risk, from which 5 outcomes (P-value for association [Pa] = .003 to <.001) survived the Holm–Bonferroni-correction, which were deemed robust. In the rs1535255 outcomes, the codominant effect (OR = 1.43, 95% CIs = 1.24–1.65, Pa < .001) had greater statistical power than the dominant effect (OR = 1.30, 95% CI = 1.08–1.57, Pa = .006). In contrast, the rs2023239 codominant outcome was underpowered. Significance of both rs806379 Caucasian outcomes (ORs = 1.20–1.43, 95% CIs = 1.07–1.57, Pa = .003) contrasted with the null effects in African-Americans (ORs = 0.98–1.08, 95% CIs = 0.70–1.53).Conclusions:Three CNR1 SNPs (rs1535255, rs2023239, and rs806379) were implicated in their associations with development of AD: based on aggregate statistical power, rs1535255 presented greater evidence for associations than rs2023239; rs806379 implicated the Caucasian subgroup. Multiple statistical and meta-analytical features (consistency, robustness, and high significance) underpinned the strengths of these outcomes. Our findings could render the CNR1 polymorphisms useful in the clinical genetics of AD.

Influence of Dopaminergic System Genetic Variation and Lifestyle Factors on Excessive Alcohol Consumption.

To examine the role of genetic and environmental factors in the pathogenesis of alcohol dependence in a Spanish cohort of women and men. We analyzed the relationship between 56 genetic variants in 7 genes associated with the dopaminergic reward pathway and excessive alcohol consumption. The study sample (N = 1533, of which 746 were women) consisted of 653 heavy consumers and 880 very low consumers from the Spanish subcohort of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Single nucleotide polymorphisms (SNPs) were genotyped using a customized array. Lifestyle variables were also examined to assess associations between genetic and environmental factors. No statistically significant differences were found between cases and controls for the allele frequencies in five genes: TH, SLC18A2, DRD1, DRD3 and COMT. Conversely, some alleles of the 12 SNPs from the DRD2 locus and the 5 from the MAOA locus showed significant associations with excessive alcohol consumption. Namely, rs10891556 (DRD2) proved to be the only SNP positively correlated with excessive alcohol consumption in both sexes. DRD2 rs1800497 and rs877138 were significantly associated in men, whereas DRD2 rs17601612 and rs4936271 and MAOA rs5906898 were associated with excessive alcohol consumption in women. A correspondence analysis provided an overall lifestyle profile of excessive drinkers, who were predominantly men who smoked, had large intakes of meat, small intakes of fruit and vegetables, whose jobs did not require high education levels and who engaged in little physical activity. It has shown the influence of dopaminergic pathway in the genetics of alcohol dependence with differences between men and women and providing a lifestyle profile of excessive drinkers.

The genetics of alcohol dependence: Twin and SNP-based heritability, and genome-wide association study based on AUDIT scores.

Alcohol dependence (AD) is among the most common and costly public health problems contributing to morbidity and mortality throughout the world. In this study, we investigate the genetic basis of AD in a Dutch population using data from the Netherlands Twin Register (NTR) and the Netherlands Study of Depression and Anxiety (NESDA). The presence of AD was ascertained via the Alcohol Use Disorders Identification Test (AUDIT) applying cut-offs with good specificity and sensitivity in identifying those at risk for AD. Twin-based heritability of AD-AUDIT was estimated using structural equation modeling of data in 7,694 MZ and DZ twin pairs. Variance in AD-AUDIT explained by all SNPs was estimated with genome-wide complex trait analysis (GCTA). A genome-wide association study (GWAS) was performed in 7,842 subjects. GWAS SNP effect concordance analysis was performed between our GWAS and a recent AD GWAS using DSM-IV diagnosis. The twin-based heritability of AD-AUDIT was estimated at 60% (55-69%). GCTA showed that common SNPs jointly capture 33% (SE = 0.12, P = 0.002) of this heritability. In the GWAS, the top hits were positioned within four regions (4q31.1, 2p16.1, 6q25.1, 7p14.1) with the strongest association detected for rs55768019 (P = 7.58 × 10(-7) ). This first GWAS of AD using the AUDIT measure found results consistent with previous genetic studies using DSM diagnosis: concordance in heritability estimates and direction of SNPs effect and overlap with top hits from previous GWAS. Thus, the use of appropriate questionnaires may represent cost-effective strategies to phenotype samples in large-scale biobanks or other population-based datasets.

Genomewide Association Study for Maximum Number of Alcoholic Drinks in European Americans and African Americans.

We conducted a genomewide association study (GWAS) for maximum number of alcoholic drinks consumed in a 24-hour period ("MaxDrinks"), in 2 independent samples comprised of over 9,500 subjects, following up on our GWAS for alcohol dependence (AD) in European Americans (EAs) and African Americans (AAs). The samples included our GWAS samples (Yale-UPenn) recruited for studies of the genetics of drug or AD, and a publicly available sample: the Study of Addiction: Genetics and Environment (SAGE). Genomewide association analysis was performed for ~890,000 single nucleotide polymorphisms (SNPs) using linear association random effects models. EAs and AAs were separately analyzed. The results confirmed significant associations of the well-known functional loci at ADH1B with MaxDrinks in EAs (rs1229984 Arg48His p=5.96×10(-15) ) and AAs (rs2066702 Arg370Cys, p=2.50×10(-10) ). The region of significant association on chromosome 4 was extended to LOC100507053 in AAs but not EAs. We also identified potentially novel significant common SNPs for MaxDrinks in EAs in the Yale-UPenn sample: rs1799876 at SERPINC1 on chromosome 1 (4.00×10(-8) ) and rs2309169 close to ANKRD36 on chromosome 2 (p=5.58×10(-9) ). After adjusting for the peak SNP rs1229984 on ADH1B, rs1799876 was nearly significant (p=1.99×10(-7) ) and rs2309169 remained highly significant (2.12×10(-9) ). The results provide further support that ADH1B modulates alcohol consumption. Future replications of potential novel loci are warranted. This is the largest MaxDrinks GWAS to date, the first in AAs.

Meta-analysis of six genes (BDNF, DRD1, DRD3, DRD4, GRIN2B and MAOA) involved in neuroplasticity and the risk for alcohol dependence

BackgroundAlcohol-related problems have a large impact on human health, accounting for around 4% of deaths and 4.5% of disability-adjusted life-years around the world. Genetic factors could explain a significant fraction of the risk for alcohol dependence (AD). Recent meta-analyses have found significant pooled odds ratios (ORs) for variants in the ADH1B, ADH1C, DRD2 and HTR2A genes. MethodsIn the present study, we carried out a meta-analysis of common variants in 6 candidate genes involved in neurotransmission and neuroplasticity: BDNF, DRD1, DRD3, DRD4, GRIN2B and MAOA. We carried out a systematic search for published association studies that analyzed the genes of interest. Relevant articles were retrieved and demographic and genetic data were extracted. Pooled ORs were calculated using a random-effects model using the Meta-Analyst program. Dominant, recessive and allelic models were tested and analyses were also stratified by ethnicity. ResultsForty two published studies were included in the current meta-analysis: BDNF-rs6265 (nine studies), DRD1-rs4532 (four studies), DRD3-rs6280 (eleven studies), DRD4-VNTR (seven studies), GRIN2B-rs1806201 (three studies) and MAOA-uVNTR (eight studies). We did not find significant pooled ORs for any of the six genes, under different models and stratifying for ethnicity. ConclusionsIn terms of the number of candidate genes included, this is one of the most comprehensive meta-analyses for genetics of AD. Pooled ORs did not support consistent associations with any of the six candidate genes tested. Future studies of novel genes of functional relevance and meta-analyses of quantitative endophenotypes could identify further susceptibility molecular factors for AD.

Genetics of Alcohol Dependence and Social Work Research: Do They Mix?

Since completion of the mapping of the human genome in early 2000, tremendous progress has been made in the identification of many different genes associated with our health and across diseases. Although social work researchers are not expected to conduct genetic research at the molecular level, it is imperative that we are able to understand the basic genetic findings related to behavioral problems and are able to translate and integrate this information into psychosocial treatment approaches and program development. This article is an introduction and overview of genetic approaches, using studies of the genetics of alcoholism to exemplify important issues. The literature review is not comprehensive and focuses primarily on the Collaborative Study on the Genetics of Alcoholism project as an example of a multidisciplinary and integrative approach to the genetic study of a major health problem often encountered in social work practice.

The genetics of alcohol dependence

Alcohol consumption dates back to the Neolithic period, and alcohol dependence contributes substantially to the current global burden of disease. Despite this, optimal therapies and preventive strategies are lacking. Formal genetic studies of alcohol dependence have shown that genetic factors play as large a role in disease etiology as environmental factors. Molecular genetic studies may identify causal factors and facilitate the development of novel preventive and therapeutic approaches. Whereas earlier studies involved the use of linkage- and candidate-gene approaches, recent years have witnessed the introduction of genome-wide association studies (GWAS). The present review provides a brief overview of the findings of formal genetic studies, summarizes the results of earlier molecular-genetic investigations, and presents a detailed overview of all published GWAS in the field of alcohol dependence research. To date, few genome-wide significant findings have been reported. However, through the polygenic approach, GWAS have both confirmed the existence of a multitude of novel risk genes and indicated interesting new candidates.

Genetics of Alcohol Dependence in Humans: Recent Findings and Perspectives

Aim: Several lines of evidence from various scientific approaches indicate that alcohol dependence (AD) in humans is genetically influenced. The aim of this review is to report recent findings, new approaches and developments in revealing the genetic underpinnings of alcohol dependence in humans. Results: Results mainly from marker-dependent studies (linkage, case-control association and genome-wide association) and intermediate phenotypes (endophenotypes) are reported as well as findings from recent pharmacogenomic and epigenetic research on alcohol use disorders. Based on the findings, potential perspectives for future research are discussed.

Genetics of alcohol dependence

Twin, family, and adoption studies have consistently shown that genetic factors play an important role in the pathogenesis of alcohol dependence. Numerous studies have aimed to identify genes that contribute to susceptibility to alcohol dependence. Whole-genome linkage studies have identified several chromosomal regions that are linked with alcohol dependence. Association studies have also identified genes associated with alcohol dependence. Alcohol-metabolizing enzymes, such as alcohol dehydrogenase-1B and aldehyde dehydrogenase-2, are the most well-established genes that have polymorphisms associated with the risk for alcohol dependence. Polymorphisms in gamma-aminobutyric acid receptor genes are also reported to be associated with alcohol dependence. The polymorphism of opioid receptor mu 1 gene is of interest because it alters the treatment effects of naltrexone. Several genes related to neural transmission have been reported to be associated with alcohol dependence, but results are inconsistent among studies. One reason for these inconsistent results is the great heterogeneity of alcohol dependence. Classifying alcohol dependence into homogeneous phenotypes is a good strategy to solve this problem. Recently, several genome-wide association studies have been reported. Genome-wide association studies enable hypothesis-free genome mapping of vulnerability-contributing genes and are expected to add data to identify genes associated with the susceptibility to alcohol dependence. Knowledge of the genetic basis of alcohol dependence is growing and leads to a better understanding of the biological mechanisms of addiction, which can help with strategies to prevent and treat this disease.

Pharmacogenetics of Alcohol and Alcohol Dependence Treatment

In this article, we review studies of genetic moderators of the response to medications to treat alcohol dependence, the acute response to alcohol, and the response to the psychotherapeutic treatment of heavy drinking. We consider four neurotransmitter systems: opioidergic, dopaminergic, GABAergic, and glutamatergic and focus on one receptor protein in each: OPRM1 (the &#micro;-opioid receptor gene), DRD4 (the D(4) dopamine receptor gene), GABRA2 (GABA(A) receptor alpha-2 subunit gene), and GRIK1 (the kainite receptor GluR5 subunit gene). We conclude that because parallel developments in alcoholism treatment and the genetics of alcohol dependence are beginning to converge, using genotypic information, it may be possible to match patients with specific treatments. Of greatest clinical relevance is the finding that the presence of an Asp40 allele in OPRM1 modestly predicts a better response to naltrexone treatment. Promising findings include the observations that a polymorphism in GABRA2 predicts the response to specific psychotherapies; a polymorphism in DRD4 predicts the effects of the antipsychotic olanzapine on craving for alcohol and drinking behavior; and a polymorphism in GRIKI predicts adverse events resulting from treatment with the anticonvulsant topiramate. Although variants in other genes have been associated with the risk for alcohol dependence, they have not been studied as moderators of the response either to treatment or acute alcohol administration. We recommend that, whenever possible, treatment trials include the collection of DNA samples to permit pharmacogenetic analyses, and that such analyses look broadly for relevant genetic variation.

Genetics of alcohol dependence

Alcohol dependence (AD), a genetically influenced phenotype, is extremely costly to individuals and to society in the United States and throughout the world, contributing to morbidity and mortality and a host of economic, interpersonal, and societal problems. Although until recently the only genes established to affect risk for AD were those encoding several alcohol metabolizing enzymes, there are now several other genes that can be regarded as confirmed risk loci, discovered through linkage and candidate gene association studies. While the mechanism of action of the effects of alcohol-metabolizing enzymes on AD risk is thought to be well understood, we are still in the early stages of understanding the physiology of other risk loci. Further, it is clear that only a small number of the many genes that influence risk for AD have been identified. Newer methodologies (e.g., genomewide association, study of copy number variation, and deep sequencing of candidate loci to identify rare risk variants) that have improved our understanding of other complex traits hold the promise of identifying a greater set of AD susceptibility loci.

Molecular Genetics of Alcohol Dependence and Related Endophenotypes

Alcohol dependence is a worldwide public health problem, and involves both environmental and genetic vulnerability factors. The heritability of alcohol dependence is rather high, ranging between 50% and 60%, although alcohol dependence is a polygenic, complex disorder.Genome-wide scans on large cohorts of multiplex families, including the collaborative study on genetics of alcoholism (COGA), emphasized the role of many chromosome regions and some candidate genes. The genes encoding the alcohol-metabolizing enzymes, or those involved in brain reward pathways, have been involved. Since dopamine is the main neurotransmitter in the reward circuit, genes involved in the dopaminergic pathway represent candidates of interest. Furthermore, gamma-amino-butyric acid (GABA) neurotransmitter mediates the acute actions of alcohol and is involved in withdrawal symptomatology. Numerous studies showed an association between variants within GABA receptors genes and the risk of alcohol dependence.In accordance with the complexity of the “alcohol dependence” phenotype, another field of research, related to the concept of endophenotypes, received more recent attention. The role of vulnerability genes in alcohol dependence is therefore re-assessed focusing on different phenotypes and endophenotypes. The latter include brain oscillations, EEG alpha and beta variants and alpha power, and amplitude of P300 amplitude elicited from a visual oddball task.Recent enhancement on global characterizations of the genome by high-throughput approach for genotyping of polymorphisms and studies of transcriptomics and proteomics in alcohol dependence is also reviewed.

The genetics of alcohol dependence

Alcohol dependence is a common, complex disorder, which affects millions of people worldwide and causes considerable burden in terms of interpersonal and societal costs. Family, twin, and adoption studies have convincingly demonstrated that genes play an important role in the development of alcohol dependence, with heritability estimates in the range of 50% to 60% for both men and women. A number of studies are under way to identify specific genes involved in the predisposition toward alcohol dependence, and there is reason to be enthusiastic about recent progress. Several associated susceptibility genes are reviewed here, including genes involved in alcohol metabolism, as well as genes involved in GABAergic, endogenous opioid, dopaminergic, cholinergic, and serotonergic transmission. The next challenge will be to further characterize the risk associated with these susceptibility genes, examining how they may be related to comorbid disorders, developmental trajectories of risk, and potential moderation by environmental factors.

Understanding and Treating Alcohol Dependence

This article represents the proceedings of a symposium presented at the 158th Annual Meeting of the American Psychiatric Association held in Atlanta, Georgia, on May 24, 2005. The organizer/chairman was Bankole A. Johnson, DSc, MD, PhD. The presentations included the following: (1) Neuropharmacological Basis of Alcohol Dependence, by George F. Koob, PhD; (2) Recent Developments in the Genetics of Alcohol Dependence, by Marc A. Schuckit, MD; (3) New Pharmacological Strategies for Treating Alcohol Dependence, by Barbara J. Mason, PhD; (4) New Medications: The Use of Anticonvulsants, Both Alone and in Combination, with Various Forms of Psychotherapy, by Bankole A. Johnson, DSc, MD, PhD; and (5) Differential Effects of Pharmacological Agents on Craving, by Nassima Ait-Daoud, MD.

Book review

The Molecular and Genetic Basis of Neurological Disease is a large volume devoted to the clinical and scientific aspects of this vast subject. There are a total of 77 chapters divided into 23 parts written by 129 authors. The subjects covered range from developmental disorders such inborn errors of amino acid metabolism and transport to degenerative disorders such as Alzheimer's disease. There are also interesting sections on the genetics of alcohol dependence, bipolar disorder and schizophrenia, human genome mapping and gene therapy.

P.1.073 The influence of trimipramine on hippocampal field potentials in the low Mg 2+-model

Alcohol-related problems have a large impact on human health, accounting for around 4% of deaths and 4.5% of disability-adjusted life-years around the world. Genetic factors could explain a significant fraction of the risk for alcohol dependence (AD). Recent meta-analyses have found significant pooled odds ratios (ORs) for variants in the ADH1B, ADH1C, DRD2 and HTR2A genes.In the present study, we carried out a meta-analysis of common variants in 6 candidate genes involved in neurotransmission and neuroplasticity: BDNF, DRD1, DRD3, DRD4, GRIN2B and MAOA. We carried out a systematic search for published association studies that analyzed the genes of interest. Relevant articles were retrieved and demographic and genetic data were extracted. Pooled ORs were calculated using a random-effects model using the Meta-Analyst program. Dominant, recessive and allelic models were tested and analyses were also stratified by ethnicity.Forty two published studies were included in the current meta-analysis: BDNF-rs6265 (nine studies), DRD1-rs4532 (four studies), DRD3-rs6280 (eleven studies), DRD4-VNTR (seven studies), GRIN2B-rs1806201 (three studies) and MAOA-uVNTR (eight studies). We did not find significant pooled ORs for any of the six genes, under different models and stratifying for ethnicity.In terms of the number of candidate genes included, this is one of the most comprehensive meta-analyses for genetics of AD. Pooled ORs did not support consistent associations with any of the six candidate genes tested. Future studies of novel genes of functional relevance and meta-analyses of quantitative endophenotypes could identify further susceptibility molecular factors for AD.