1. ¹Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
2. ²VA Connecticut Healthcare System, West Haven Campus, CT, USA
3. ³Department of Psychiatry, Alcohol Research Center, University of Connecticut School of Medicine, Farmington, CT, USA

Correspondence: Dr J Gelernter, Yale University School of Medicine, VA Psychiatry 116A2, 950 Campbell Avenue, West Haven, CT 06516, USA. Tel: +1 203 932 5711 ext. 3590; Fax: +1 203 937 3897; E-mail: joel.gelernter@yale.edu

Received 4 April 2005; Revised 19 July 2005; Accepted 30 August 2005; Published online 12 October 2005.

Abstract

The alcohol dehydrogenase (ADH) family constitutes one of the key sets of enzymes responsible for the oxidation of alcohol. The ADH4 gene, an important member of this family, is a functional and positional candidate for alcohol dependence. The present study aimed to investigate the relationship between ADH4 gene variation and alcohol dependence and drug dependence in European-Americans (EAs) and African-Americans (AAs). Seven single nucleotide polymorphisms (SNPs) spanning the ADH4 gene were genotyped in 365 healthy controls (317 EAs and 48 AAs) and 561 subjects (400 EAs and 161 AAs) affected with alcohol dependence and/or drug dependence (436 with alcohol dependence; 356 with drug dependence). Hardy–Weinberg equilibrium (HWE) for the genotype frequency distributions of these markers was tested in all phenotype groups to evaluate association between ADH4 gene variation and phenotypes and to fine-map the disease risk locus. The allele, genotype, and haplotype frequency distributions of these markers were compared between cases and controls to confirm the associations. The genotype frequency distributions of ADH4 markers were in HWE in EA controls, but were in Hardy–Weinberg disequilibrium (HWD) (ie, deviation from HWE) in EA cases. Among all markers, SNP2 (rs1042363) at exon 9 or SNP6 (rs1800759) at the promoter showed the greatest degree of HWD, among patients with either alcohol dependence or drug dependence. Significant differences between EA cases and controls were seen for genotype (10^-6<global p<0.044), but not any allele or haplotype, frequency distributions for all seven ADH4 markers. These findings suggest that ADH4 genotypes predispose to alcohol dependence and drug dependence in a recessive manner, a predisposition that is population specific. SNP2 or SNP6 was the marker genetically closest to the functional risk loci for both alcohol dependence and drug dependence.