Abstract
The common variant rs1344706 within the zinc-finger protein gene ZNF804A has been strongly implicated in schizophrenia (SZ) susceptibility by a series of recent genetic association studies. Although associated with a pattern of altered neural connectivity, evidence that increased risk is mediated by an effect on cognitive deficits associated with the disorder has been equivocal. This study investigated whether the same ZNF804A risk allele was associated with variation in the P300 auditory-evoked response, a cognitively relevant putative endophenotype for SZ. We compared P300 responses in carriers and noncarriers of the ZNF804A risk allele genotype groups in Irish patients and controls (n=97). P300 response was observed to vary according to genotype in this sample, such that risk allele carriers showed relatively higher P300 response compared with noncarriers. This finding accords with behavioural data reported by our group and others. It is also consistent with the idea that ZNF804A may have an impact on cortical efficiency, reflected in the higher levels of activations required to achieve comparable behavioural accuracy on the task used.
Highlights
A single-nucleotide polymorphism (SNP) rs1344706 located within zinc-finger binding protein 804A (ZNF804A) was the first genetic variant to achieve genome-wide significance for psychosis.[1]
No differences were observed between risk carriers and non-risk carriers in either positive symptom severity, negative symptom severity or years since diagnosis, consistent with our earlier report on the clinical effects of ZNF804A based on a sample of ~1000 cases.[32]
No significant behavioural differences in P300 task performance were observed between genotype groups (AA versus a psychiatrist (AC)+CC) either for the total number of targets presented or the number of correct responses or the number of errors made (Table 2)
Summary
In addition to the common variants identified, evidence of excess copy number variants at the ZNF804A locus in psychiatric cases has been reported,[8] rare non-synonymous ZNF804A risk variants have yet to be identified.[9] Following de novo polymorphism discovery and detailed association analysis in the Williams et al.,[7] meta-analysis, rs1344706 remained the most strongly associated marker in the gene. Consisting of four exons and transcribing a protein of 1210 amino acids, ZNF804A is brain expressed but is of unknown function Proteins with this zinc-finger domain were originally identified as DNA-binding molecules with a role in transcription but have diverse interactions with many molecules including RNA and proteins. The risk allele has been associated with a pattern of altered functional connectivity in several brain regions, including the dorsolateral pre-frontal cortex, the hippocampus and the amygdala in a sample of healthy participants.[11,12]
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