Molecular Genetics of Alcohol Dependence and Related Endophenotypes

Yann   L.   Strat; Nicolas      Ramoz; Gunter      Schumann; Philip      Gorwood

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 alcoholmetabolizing 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.

Keywords: Alcohol dependence, association, dopamine, endophenotype, GABA, linkage, proteomics, transcriptomics