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. 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.

Forensic Value of Genetic Variants Associated with Anti-Social Behavior

“…Genes encoding zinc finger proteins ( ZNF ) have also been associated with abnormal and/or criminal behavior. For example, some polymorphisms of ZNF804A gene have been associated with drug abuse in European Americans, while Tiihonen et al reported that, in the brains of violent offenders, ribosomal pseudogene RPL10P9 and ZNF132 were upregulated [ 74 , 75 ].…”

Genome-Wide Meta-Analyses of FTND and TTFC Phenotypes

“…Our convergent analyses identified several intriguing genes in addition to those previously highlighted for ND (CHRNA5-CHRNA3-CHRNB4, CHRNB3-CHRNA6, and CHRNA4 6 ). These included genes previously associated with diseases for which cigarette smoking is a significant risk factor, such as cocaine addiction (RBFOX1), 42 alcohol dependence (THSD7B), 43 schizophrenia (ZNF804A) 44 and heroin addiction 45,46 (ZNF804A), rheumatoid arthritis (PDE2A), 47 and prostate cancer (APOL3) 48 (Table 3). Furthermore, RBFOX1 was highlighted in a recent study on the genetic relationship between schizophrenia and ND.…”

Human Genetics of Addiction: New Insights and Future Directions

“…Polygenic risk scores based on GWAS-identified variants for schizophrenia or bipolar disorder have shown significant associations with smoking, alcohol, and substance use disorder phenotypes [123–125]. Early examples of genetic variants that demonstrate such pleiotropy, i.e., exert effects on more than one outcome, across addiction and other psychiatric diseases include: ZNF804A SNP rs1344706, the first genome-wide significant finding for schizophrenia [126] and later extended to heroin addiction [127, 128]; and the BDNF SNP rs6265 and CHRNA5 SNPs rs16969968 and rs1051730 implicated at genome-wide significance for smoking (Table 1) and extended to schizophrenia/bipolar disorder outcomes [129, 130]. As the sample sizes for addiction GWAS expand to sizes comparable with other psychiatric disease GWAS, polygenic risk scores and top loci that comprise these scores are likely to reveal even more extensive sharing.…”