Alcohol dependence is associated with the ZNF699 gene, a human locus related to Drosophila hangover, in the Irish affected sib pair study of alcohol dependence (IASPSAD) sample

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 (v 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.

The Genetics of Alcohol Responses of Invertebrate Model Systems

“…ZNF699 is one of the human homologs of the hangover gene, and in an Irish sib pair study, polymorphisms in ZNF699 were associated with alcohol dependence. One of the dependence-associated haplotypes also showed decreased ZNF699 gene expression in the dorsolateral prefrontal cortex in postmortem tissue (Riley et al, 2006).…”

Drosophila melanogaster as a model to study drug addiction

“…Polymorphisms in the human ALK gene are correlated with multiple measures of ethanol sensitivity (Lasek et al 2011b), and polymorphisms in one human homolog of hang , ZNF699 , were found to be associated with alcohol dependence (Riley et al 2006). Recently, a genome-wide meta-analysis revealed that polymorphisms in autism susceptibility candidate 2 ( AUTS2 ) are associated with alcohol consumption (Schumann et al 2011).…”

Ethanol‐Regulated Genes That Contribute to Ethanol Sensitivity and Rapid Tolerance in Drosophila

“…Genetic and pharmacologic studies indicate that rapid tolerance in Drosophila requires the integrity of octopaminergic and γ-aminobutyric acid B (GABA B ) receptor pathways, a large conductance calcium-sensitive potassium (BK) channel, the Homer neuronal adaptor protein, and a novel stress pathway defined by the gene hangover (Cowmeadow et al, 2005; Dzitoyeva et al, 2003; Scholz et al, 2005; Urizar et al, 2007). Thus, at least some of the neurotransmitter and signaling systems that mediate these behaviors are evolutionarily conserved (e.g., the GABA B and BK-type potassium channels; Pietrzykowski et al, 2004; Zaleski et al, 2001), and studies in flies can provide novel candidate genes for mammalian and human studies (Riley et al, 2006). …”