The schizophrenia risk gene ZNF804A: clinical associations, biological mechanisms and neuronal functions

ZNF804A (zinc-finger protein 804A) has been recognized as a schizophrenia risk gene across multiple world populations. Its intronic single-nucleotide polymorphism (SNP) rs1344706 is among one of the strongest susceptibility variants that have achieved genome-wide significance in genome-wide association studies (GWAS) for schizophrenia and has been widely and intensively studied. To elucidate the biological mechanisms underlying the genetic risk conferred by rs1344706, we retrospectively analyzed the progresses in brain gene expression quantitative trait loci (eQTL) analyses, ZNF804A-induced pathway alterations in neural cells and changes in synaptic phenotypes associated with ZNF804A expression. Based on these data, we hypothesize a potential biological mechanism for a genetic risk allele of ZNF804A in schizophrenia pathogenesis. We also review the efforts being made to characterize the affected intermediate phenotypes using neuroimaging and neuropsychological approaches. We then discuss additional common and rare ZNF804A variants in schizophrenia susceptibility and the potential genetic heterogeneity of these genomic loci between Europeans and Asians. This review for we believe the first time systematically presents the evidence for ZNF804A, describing its discovery and likely roles in brain development and schizophrenia pathogenesis. We believe that this work has summarized this information with a systemic and broad assessment of recent findings.