GAD67 gene and alcoholism. An association study between single nucleotide polymorphism and alcohol dependence

Alcoholism is one of the major social, economic and public health problems facing the world today. Social drinking can be associated with development of alcohol tolerance, leading in turn to abuse and dependence. Primary features of alcoholism include loss of control over consumption, obsessional thoughts about the next drink, and continuation of abuse despite negative health effects and social consequences. Epidemiologically alcoholism is defined as a heterogeneous, complex disorder with both genetic and environmental influences. A meta-analysis of twin studies has shown that the genetic influence of all addictive substances ranges from 40–70% and the heritability of alcoholism, derived from nearly 10000 twin pairs, is found to be 50%, showing that genetic and environmental risk factors for alcoholism are almost equally important although they may differ in the different populations. Additionally alcoholism is a disease with an underlying complex of biochemical pathophysiology. Unlike other addictive drugs, alcohol has widespread effects throughout the brain; it acts at a variety of targets within cell membranes and in the intracellular signal transduction, inducing effects on neurotransmitter and neurohormone membrane receptors and receptor-gated and voltage-activated ion channels. In the central nervous system, ethanol alters the activity of several neurotransmitters including monoamines and gamma-aminobutyric acid 2 (GABA). Genetic vulnerability to alcoholism is therefore likely due to a number of genes of small varying degrees in many neurotransmitter systems and signal transduction pathways. In particular, several studies suggest that GABA may be involved in alcohol withdrawal and tolerance; the genes encoding for glutamate decarboxylase (GAD), the rate-limiting enzyme in GABA synthesis, are of potential interest for their association to ethanol consumption and alcohol dependence. In our project we evaluated, in a case-control association study, the relationship between the GAD gene and alcohol use disorder. Specifically, the total cohort analyzed was 283 male individuals, 107 of which were alcohol dependent subjects and 176 controls. As a whole, in all experiments carried out a total of 26 single nucleotide polymorphisms (SNPs) localized in the promoter, exonic and intronic regions of the GAD 67 gene by using GenomeLab SNPStream Genotyping System technology were analyzed. Our results showed a significant difference in genotype distribution of one SNP (rs 11542313) localized in the exon 3 of the GAD 67 gene that is responsible for a silent mutation (His-His).