Polymorphism in the ZNF804A Gene and Variation in D₁ and D₂/D₃ Dopamine Receptor Availability in the Healthy Human Brain: A Dual Positron Emission Tomography Study

Background: The rs1344706 single nucleotide polymorphism in the ZNF804A gene has been associated with risk for psychosis in multiple genome-wide association studies, yet mechanisms underlying this association are not known. Given preclinical work suggesting an impact of ZNF804A on dopamine receptor gene transcription and clinical studies establishing dopaminergic dysfunction in patients with schizophrenia, we hypothesized that the ZNF804A risk single nucleotide polymorphism would be associated with variation in dopamine receptor availability in the human brain. Methods: In this study, 72 healthy individuals genotyped for rs1344706 completed both [¹⁸F]fallypride and [¹¹C]NNC-112 positron emission tomography scans to measure D₂/D₃ and D₁ receptor availability, respectively. Genetic effects on estimates of binding potential for each ligand were tested first with canonical subject-specific striatal regions of interest analyses, followed by exploratory whole-brain voxelwise analyses to test for more localized striatal signals and for extrastriatal effects. Results: Region of interest analyses revealed significantly less D₂/D₃ receptor availability in risk-allele homozygotes (TT) compared with non-risk allele carriers (G-allele carrier group: TG and GG) in the associative striatum and sensorimotor striatum, but no significant differences in striatal D₁ receptor availability. Conclusions: These data suggest that ZNF804A genotype may be meaningfully linked to dopaminergic function in the human brain. The results also may provide information to guide future studies of ZNF804A-related mechanisms of schizophrenia risk.