Replication of ZNF804A gene variant associations with risk of heroin addiction

Abstract

Heroin addiction is heritable, but few specific genetic variants have been reproducibly associated with this disease. The zinc finger protein 804A (ZNF804A) gene is a biologically plausible susceptibility gene for heroin addiction, given its function as a transcription factor in human brain and strong indications for psychiatric diseases that have high comorbidity with heroin addiction. Novel associations of two common ZNF804A single nucleotide polymorphisms (SNPs), rs7597593 and rs1344706, with heroin addiction have been reported in Han Chinese. Both SNPs have also been implicated for regulating ZNF804A expression in human brain, including the addiction-relevant dorsolateral prefrontal cortex. In this independent replication study, we tested the rs7597593 and rs1344706 SNP genotypes and their corresponding haplotypes for association with heroin addiction using cases drawn from the Urban Health Study and population controls: total N=10,757 (7,095 European Americans and 3,662 African Americans). We independently replicated both ZNF804A SNP associations in European Americans: the rs7597593-T (P=0.016) and rs1344706-A (P=0.029) alleles both being associated with increased risk of heroin addiction, consistent with the prior report. Neither SNP was associated in African Americans alone, but meta-analysis across both ancestry groups resulted in significant associations for rs1344706-A (P=0.016, odds ratio [95% confidence interval] = 1.13 [1.02-1.25]) and its haplotype with rs7597593-T (P=0.0067, odds ratio [95% confidence interval] = 1.16 [1.04-1.29]). By demonstrating consistent associations across independent studies and diverse ancestry groups, our study provides evidence that these two ZNF804A SNPs and their risk haplotype are among the few replicable genetic associations with heroin addiction