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

Abstract

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.

Zinc Finger Proteins in Neuro-Related Diseases Progression

“…Studies have shown that MSUT2 knockout has anti-inflammatory and neuroprotective effects in a mouse model. The flowchart is Frankel et al, 1987;Wolfe et al, 2000;Schefe et al, 2006;Brayer et al, 2008;Town et al, 2009;Fan et al, 2012;Shi et al, 2013;Yuan et al, 2013;Xu et al, 2016;Yu et al, 2017;Brahmachari et al, 2019;Kruszka et al, 2019;Lorsch et al, 2019;Ohkubo et al, 2019;Zhang et al, 2019;Choi et al, 2020;Deshpande et al, 2020;Hu et al, 2020;Xiao et al, 2020;Dentici et shown in Figure 1. Loss of function of MSUT2 can reduce the formation of tau protein and protect the loss of neurons, but the molecular mechanism is still unclear.…”

A framework for an evidence-based gene list relevant to autism spectrum disorder

“…Fig 3.Systematic evaluation of quality of the ASD phenotype report. Six phenotype experts independently scored eight published reports[100][101][102][103][104][105][106][107] using this algorithm; results indicated 98% consistency regarding the rating of low, medium and high confidence in the reported ASD phenotype, and 90% consistency regarding the cognitive ability information. Proposed scoring adjustments: If default score is 2 (ClinGen default for de novo variant): low confidence (-1) and medium confidence (-0.5); if default score is 1.5 (ClinGen default for an inherited variant that is predicted/proven null): low confidence (-0.5) and medium confidence (-0.25); if default score is 0.5 (ClinGen default for an inherited variant not predicted/proven null, with some evidence of gene impact, e.g.…”

Family-based association study of ZNF804A polymorphisms and autism in a Han Chinese population

“…However, these SNPs showed no polymorphism in the CHB population. Recently, one study found that rs10497655 in ZNF804A was significantly associated with ASD (OR = 1.20 (95%CI 1.05–1.37), P = 0.007851) in a Han Chinese cohort (854 cases and 926 controls) and the T risk allele homozygotes of rs10497655 could reduce ZNF804A expression [46]. On the other hand, Griswold et al found duplications of CNVs in ZNF804A only in autistic individuals [47].…”