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Analysis of schizophrenia-related genes and electrophysiological measures reveals ZNF804A association with amplitude of P300b elicited by novel sounds.

ABSTRACT: Several genes have recently been identified as risk factors for schizophrenia (SZ) by genome-wide association studies (GWAS), including ZNF804A which is thought to function in transcriptional regulation. However, the downstream pathophysiological changes that these genes confer remain to be elucidated. In 143 subjects (68 clinical high risk, first episode or chronic cases; 75 controls), we examined the association between 21 genetic markers previously identified by SZ GWAS or associated with putative intermediate phenotypes of SZ against three event-related potential (ERP) measures: mismatch negativity (MMN), amplitude of P300 during an auditory oddball task, and P300 amplitude during an auditory novelty oddball task. Controlling for age and sex, significant genetic association surpassing Bonferroni correction was detected between ZNF804A marker rs1344706 and P300 amplitude elicited by novel sounds (beta=4.38, P=1.03 × 10(-4)), which is thought to index orienting of attention to unexpected, salient stimuli. Subsequent analyses revealed that the association was driven by the control subjects (beta=6.35, P=9.08 × 10(-5)), and that the risk allele was correlated with higher novel P300b amplitude, in contrast to the significantly lower amplitude observed in cases compared to controls. Novel P300b amplitude was significantly correlated with a neurocognitive measure of auditory attention under interference conditions, suggesting a relationship between novel P300b amplitude and higher-order attentional processes. Our results suggest pleiotropic effects of ZNF804A on risk for SZ and neural mechanisms that are indexed by the novel P300b ERP component.

SUBMITTER: Del Re EC

PROVIDER: S-EPMC3905227 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Analysis of schizophrenia-related genes and electrophysiological measures reveals ZNF804A association with amplitude of P300b elicited by novel sounds.

Del Re E C EC Bergen S E SE Mesholam-Gately R I RI Niznikiewicz M A MA Goldstein J M JM Woo T U TU Shenton M E ME Seidman L J LJ McCarley R W RW Petryshen T L TL

Translational psychiatry 20140114

Several genes have recently been identified as risk factors for schizophrenia (SZ) by genome-wide association studies (GWAS), including ZNF804A which is thought to function in transcriptional regulation. However, the downstream pathophysiological changes that these genes confer remain to be elucidated. In 143 subjects (68 clinical high risk, first episode or chronic cases; 75 controls), we examined the association between 21 genetic markers previously identified by SZ GWAS or associated with put ...[more]

PMID: 24424392

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Project description:Abstract Background: Following both meta-analysis and extensive resequencing, the single-nucleotide polymorphism of allele A, rs1344706, located in intron 2 of the zinc-finger protein gene ZNF804A, continues to be the common variant most strongly associated with schizophrenia risk (P = 1.1_10–13). ZNF804a is highly expressed in adult brain and functional effects on both protein expression, and altered DNA–protein interaction have been reported. In addition, the ZNF804A rs1344706 A allele has recently been reported to be associated with worse clinical outcome. We were interested in examining whether another proxy for worse clinical outcome, the Positive and Negative Syndrome Scale (PANSS) excitement factor, is associated with a ZNF804a genotype. We hypothesized that a single-nucleotide polymorphism in ZNF804a could be associated with impulsivity. The aim of this study was to assess the association of a single-nucleotide polymorphism rs1344706 with the PANSS excitement factor. Methods: We tested the effect of rs1344706 (A/C) genotype in 133 individuals with DSM-5 chronic schizophrenia using the PANSS. Scores on the PANSS excitement factor were compared between individuals who expressed allele A and those who expressed allele C (individuals with the heterogeneous allele A/C were combined to the C group). General Linear Model (GLM) was used to analyze the differences between groups for the PANSS Excitement Factor (assessed by the summation of: excitement, hostility, uncooperativeness, and poor impulse control). Results: A total of 133 subjects were sampled for ZNF804; however, PANSS data were available for 122 subjects. Of the 122, 68.85% (n = 84) of subjects presented with allele A and 31.15% (n = 38) with allele C. In all, 67.85% (n = 57) of the individuals with allele A were African Americans, and 28.95% (n = 11) of individuals with allele C were African Americans, and 39.47% (n = 15) were Hispanics. The PANSS total score for the entire sample was 72.64 (SD = 9.33). PANSS excitement factor scores ranged from 4 to 15 in group A and 4 to 14 in group C. GLM analysis showed a significant difference in ZNF804, F(1, 121) = 5.595, P = .020, between individuals with allele A compared to those with allele C. The mean excitement factor score for allele A was lower (mean = 7.762, SE = 0.273) than for allele C group (mean = 8.921, SE = 0.427). Conclusion: While the risk “A” allele at rs1344706 has been associated with altered functional brain connectivity and represents a risk factor for psychosis, our results shows an association of the “C” allele at rs1344706 with impulsivity in chronic schizophrenia patients. The difference in our findings when compared to previous reports may have to do with the differing ethnic distribution of our population, which is predominantly African American. This finding could be of nosological value for biological subtyping across the spectrum of schizophrenia, although important limitations should be noted such as small sample size and lack of ethnic diversity of our population.

Dataset Information

Analysis of schizophrenia-related genes and electrophysiological measures reveals ZNF804A association with amplitude of P300b elicited by novel sounds.

Publications

Analysis of schizophrenia-related genes and electrophysiological measures reveals ZNF804A association with amplitude of P300b elicited by novel sounds.

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