1. ¹Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA
2. ²Department of Human Genetics, Virginia Commonwealth University, Richmond, VA, USA
3. ³Shaftesbury Square Hospital, Belfast, Northern Ireland
4. ⁴Department of Genetics, University of North Carolina, Chapel Hill, NC, USA
5. ⁵Health Research Board, Dublin, Ireland
6. ⁶Department of Psychology, University of Southern California, Los Angeles, CA, USA

Correspondence: Dr BP Riley, VIPBG, Department of Psychiatry, Virginia Commonwealth University, 800 E Leigh Street, PO Box 980424, Richmond, VA 23298-0424, USA. E-mail: bpriley@vcu.edu

⁷These authors contributed equally to this work.

Received 6 May 2006; Accepted 28 June 2006; Published online 29 August 2006.

Abstract

Because tolerance is an important aspect of alcohol dependence (AD) in humans, recent evidence showing that the Drosophila gene hang is critically involved in the development of alcohol tolerance in the fly suggests that variation in related human loci might be important in the etiology of alcohol-related disorders. The orthology of hang in mammals is complex, but a number of human gene products (including ZNF699) with similar levels of amino-acid identity (18–26%) and similarity (30–41%), are consistently identified as the best matches with the translated hang sequence. We tested for association between the dichotomous clinical phenotype of alcohol dependence and seven single nucleotide polymorphisms (SNPs) in ZNF699 in our sample of 565 genetically independent cases and 496 siblings diagnosed with AD, and 609 controls. In analyses of genetically independent cases and controls, four of the seven single markers show strong evidence for association with AD (0.00003<Fisher's exact P<0.001), and the most significant single marker, rs7254880, tags an associated haplotype with frequency 0.071 in cases compared to 0.034 in controls (² 15.563, P<0.00008, 5000 permutation P<0.001, OR 2.17); inclusion of affected siblings gives similar results. Expression analyses conducted in independent postmortem brain samples show that expression of ZNF699 mRNA is significantly reduced in the dorsolateral prefrontal cortex of individuals carrying this haplotype compared with other observed haplotype combinations.