The mechanism underlying ZNF804A function in human brain and heroin addiction risk is not known. However, rs1344706 has strong potential for influencing the ZNF804A gene, and its further characterization may help to elucidate the disease-relevant mechanism. The rs1344706-A risk allele maintains the predicted binding sites for two transcription factors expressed in the brain (Myt1L and POU3F1/Oct-6), and it has been associated with increased ZNF804A mRNA expression in postmortem dorsolateral prefrontal cortex, a highly relevant brain region for addiction (Goldstein & Volkow, 2011), from psychiatrically normal controls (Riley et al., 2010). An allelic specific expression study further suggested that rs1344706 directly affects ZNF804A expression in this brain region (Guella et al., 2014). ZNF804A functions as a transcription factor that regulates genes in the dopaminergic pathway (Girgenti et al., 2012), so increased ZNF804A mRNA expression would be expected to alter downstream effects on dopamine release and synthesis and contribute to heroin addiction risk. Additionally, ZNF804A is most highly expressed in human brain during the fetal period, and rs1344706 has been shown to affect expression of a novel splice variant of ZNF804A that is specific to fetal brain (Tao et al., 2014). This splicing mechanism could underlie the rs1344706 association with heroin addiction.
