Dataset Information

Molecular genetics of alcohol dependence and related endophenotypes.

ABSTRACT: 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.

SUBMITTER: Strat YL

PROVIDER: S-EPMC2691669 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Molecular genetics of alcohol dependence and related endophenotypes.

Strat Yann L YL Ramoz Nicolas N Schumann Gunter G Gorwood Philip P

Current genomics 20081101 7

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-m ...[more]

PMID: 19506733

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Project description:BACKGROUND:While genetic influences on alcohol dependence (AD) are substantial, progress in the identification of individual genetic variants that impact on risk has been difficult. METHODS:We performed a genome-wide association study on 3,169 alcohol consuming subjects from the population-based Molecular Genetics of Schizophrenia (MGS2) control sample. Subjects were asked 7 questions about symptoms of AD which were analyzed by confirmatory factor analysis. Genotyping was performed using the Affymetrix 6.0 array. Three sets of analyses were conducted separately for European American (EA, n = 2,357) and African-American (AA, n = 812) subjects: individual single nucleotide polymorphisms (SNPs), candidate genes and enriched pathways using gene ontology (GO) categories. RESULTS:The symptoms of AD formed a highly coherent single factor. No SNP approached genome-wide significance. In the EA sample, the most significant intragenic SNP was in KCNMA1, the human homolog of the slo-1 gene in C. Elegans. Genes with clusters of significant SNPs included AKAP9, phosphatidylinositol glycan anchor biosynthesis, class G (PIGG), and KCNMA1. In the AA sample, the most significant intragenic SNP was CEACAM6 and genes showing empirically significant SNPs included KCNQ5, SLC35B4, and MGLL. In the candidate gene based analyses, the most significant findings were with ADH1C, nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1) and ankyrin repeat and kinase domain containing 1 (ANKK1) in the EA sample, and ADH5, POMC, and CHRM2 in the AA sample. The ALIGATOR program identified a significant excess of associated SNPs within and near genes in a substantial number of GO categories over a range of statistical stringencies in both the EA and AA sample. CONCLUSIONS:While we cannot be highly confident about any single result from these analyses, a number of findings were suggestive and worthy of follow-up. Although quite large samples will be needed to obtain requisite power, the study of AD symptoms in general population samples is a viable complement to case-control studies in identifying genetic risk variants for AD.

Project description:BackgroundThe tradition of consuming alcohol has long been a part of Italian culture and is responsible for a large health burden. This burden may be reduced with effective interventions, one of the more important of which is treatment for Alcohol Dependence (AD). The aim of this article is to estimate the burden of disease in Italy attributable to alcohol consumption, heavy alcohol consumption, and AD. An additional aim of this paper is to examine the effects of increasing the coverage of treatment for AD on the alcohol-attributable burden of disease.MethodsAlcohol-attributable deaths and the effects of treatments for AD were estimated using alcohol-attributable fractions and simulations. Deaths, potential years of life lost, years lived with disability, and disability adjusted life years lost were obtained for 2004 for Italy and for the European Union from the Global Burden of Disease study. Alcohol consumption data were obtained from the Global Information System on Alcohol and Health. The prevalences of current drinkers, former drinkers, and lifetime abstainers were obtained from the GENder Alcohol and Culture International Study. The prevalence of AD was obtained from the World Mental Health Survey. Alcohol relative risks were obtained from various meta-analyses.Results5,320 deaths (1,530 female deaths; 3,790 male deaths) or 5.9% of all deaths (4.9% of all female deaths; 6.3% of all male deaths) of people 15 to 64 years of age were estimated to be alcohol-attributable. Of these deaths, 74.5% (61.3% for females; 79.8% for males) were attributable to heavy drinking, and 26.9% (25.6% for females; 27.5% for males) were attributable to AD. Increasing pharmacological AD treatment coverage to 40% would result in an estimated reduction of 3.3% (50 deaths/year) of all female and 7.6% (287 deaths/year) of all male alcohol-attributable deaths.ConclusionsAlcohol was responsible for a large proportion of the burden of disease in Italy in 2004. Increasing treatment coverage for AD in Italy could reduce that country's alcohol-attributable burden of disease.

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Molecular genetics of alcohol dependence and related endophenotypes.

Publications

Molecular genetics of alcohol dependence and related endophenotypes.

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