A promoter variant in ZNF804A decreasing its expression increases the risk of autism spectrum disorder in the Han Chinese population.

Synaptic pathology may be one of the cellular substrates underlying autism spectrum disorder (ASD). ZNF804A is a transcription factor that can affect or regulate the expression of many candidate genes involved in ASD. It also localizes at synapses and regulates neuronal and synaptic morphology. So far, few reports have addressed possible associations between ZNF804A polymorphisms and ASD. This study aimed to investigate whether ZNF804A genetic variants contribute to ASD susceptibility and its possible pathological role in the disorder. We analyzed the relationship of two polymorphisms (rs10497655 and rs34714481) in ZNF804A promoter region with ASD in 854 cases versus 926 controls. The functional analyses of rs10497655 were then performed using real-time quantitative polymerase chain reaction, electrophoretic mobility shift assays, chromatin immunoprecipitation and dual-luciferase assays. The variant rs10497655 was significantly associated with ASD (P = 0.007851), which had a significant effect on ZNF804A expression, with the T risk allele homozygotes related with reduced ZNF804A expression in human fetal brains. HSF2 acted as a suppressor by down-regulating ZNF804A expression and had a stronger binding affinity for the T allele of rs10497655 than for the C allele. This was the first experiment to elucidate the process in which a disease-associated SNP affects the level of ZNF804A expression by binding with the upstream regulation factor HSF2. This result indicates that the rs10497655 allelic expression difference of ZNF804A during the critical period of brain development may have an effect on postnatal phenotypes of ASD. It reveals new roles of ZNF804A polymorphisms in the pathogenesis of psychiatric disorders.