Zinc Finger Protein 804A (ZNF804A) and Verbal Deficits in Individuals With Autism

J Psychiatry Neurosci. 2014 Sep;39(5):294-303. doi: 10.1503/jpn.130126.

Abstract

Background: In a genome-wide association study of autism, zinc finger protein 804A (ZNF804A) single nucleotide polymorphisms (SNPs) were found to be nominally associated in verbally deficient individuals with autism. Zinc finger protein 804A copy number variations (CNVs) have also been observed in individuals with autism. In addition, ZNF804A is known to be involved in theory of mind (ToM) tasks, and ToM deficits are deemed responsible for the communication and social challenges faced by individuals with autism. We hypothesized that ZNF804A could be a risk gene for autism.

Methods: We examined the genetic association and CNVs of ZNF804A in 841 families in which 1 or more members had autism. We compared the expression of ZNF804A in the postmortem brains of individuals with autism (n = 8) and controls (n = 13). We also assessed in vitro the effect of ZNF804A silencing on the expression of several genes known to be involved in verbal efficiency and social cognition.

Results: We found that rs7603001 was nominally associated with autism (p = 0.018). The association was stronger (p = 0.008) in the families of individuals with autism who were verbally deficient (n = 761 families). We observed ZNF804A CNVs in 7 verbally deficient boys with autism. In ZNF804A knockdown cells, the expression of synaptosomal-associated protein, 25kDa (SNAP25) was reduced compared with controls (p = 0.009). The expression of ZNF804A (p = 0.009) and SNAP25 (p = 0.009) were reduced in the anterior cingulate gyrus (ACG) of individuals with autism. There was a strong positive correlation between the expression of ZNF804A and SNAP25 in the ACG (p < 0.001).

Limitations: Study limitations include our small sample size of postmortem brains.

Conclusion: Our results suggest that ZNF804A could be a potential candidate gene mediating the intermediate phenotypes associated with verbal traits in individuals with autism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Autistic Disorder / genetics*
  • Autistic Disorder / metabolism*
  • Brain / metabolism*
  • Cell Line, Tumor
  • Child
  • Child, Preschool
  • DNA Copy Number Variations
  • Family
  • Female
  • Gene Silencing
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genotyping Techniques
  • Gyrus Cinguli / metabolism
  • Humans
  • Kruppel-Like Transcription Factors / genetics*
  • Kruppel-Like Transcription Factors / metabolism*
  • Language*
  • Male
  • Polymorphism, Single Nucleotide
  • Synaptosomal-Associated Protein 25 / metabolism
  • Young Adult

Substances

  • Kruppel-Like Transcription Factors
  • SNAP25 protein, human
  • Synaptosomal-Associated Protein 25
  • ZNF804A protein, human