The region of strongest association with alcohol dependence extended from intron 3 past the 3' end of GABRA2; all 43 of the consecutive three-SNP haplotypes in this region of GABRA2 were highly significant.
There was evidence of association to alcohol dependence for seven adjacent markers spanning 98,000 bp in the middle and 3'-portion of the GABRA2 gene (range of P-values = 0.008-0.03).
Based on a haplotypic association of alcohol dependence with the gene encoding the GABA(A) receptor alpha-2 subunit (GABRA2), we examined whether GABRA2 alleles are associated with the subjective response to alcohol.
Non-coding variations in GABRA2, the gene encoding the alpha2 subunit, are associated with the risk for alcoholism, suggesting that regulatory differences are important.
In this paper we summarize published results from linkage and association analyses of two chromosomal regions in which the use of endophenotypes has successfully led to the identification of genes associated with alcohol dependence [GABRA2 (Edenberg et al., (2004).Am.J. Hum.Genet.
Although our study was limited by the number of cases being larger than the number of controls, the results confirm GABRA2 as a susceptibility gene for alcohol dependence in the German population.
Logistic regression analysis indicated that genetic elements in the GABRG1 haplotype block likely contribute to AD risk in an additive manner, whereas those in the GABRA2 haplotype block may act in a dominant manner in relation to risk of AD.
Previous studies demonstrated, and replicated, an association between single nucleotide polymorphisms (SNPs) within the GABRA2 gene and risk for alcohol dependence.
The GABRA2 locus has been found to be associated with alcohol dependence in several studies, but no functional variant that can account for this association has been identified.
In summary, these results extend previous findings and provide new insights into the putative biobehavioral mechanisms that may moderate the association between the GABRA2 gene, sensitivity to the acute effects of alcohol and ultimately alcohol dependence.
The GABRA2 allelic associations found in clinical case-control studies have detectable but minor effects on DSM-defined alcohol dependence in the general community.
These results demonstrated that GABRA2--originally associated with a diagnosis of alcohol dependence in adults--also predicted the onset of symptoms among subjects in their 20s, confirmed specific hypotheses about three other predictors in the fi nal model, and suggested the utility of incorporating biological and nonbiological predictors to optimally predict young adult alcohol problems.
We describe analyses aimed at characterizing the pathway of risk associated with GABRA2, a gene previously associated with adult alcohol dependence, in a community sample of children followed longitudinally from childhood through young adulthood.