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.

Elevated P3b latency variability in carriers of ZNF804A risk allele for psychosis

“…Firstly there are no significant differences between groups in median amplitude (c.f. O'Donoghue et al, 2014;Del Re et al, 2014). Secondly even when controlling for non-significant differences, our effects hold.…”

“…Evidence is mixed on its structural correlates -some studies find no association of rs1344706 and volumetric measures (Cousijn et al, 2014;Sprooten et al, 2012) or white matter integrity (Kuswanto et al, 2012;Wei et al, 2013), while others find associations with white matter volume (Wassink and Epping, 2012), white matter integrity (Ikuta et al, 2014), or grey matter volume . ERP studies have also identified elevated auditory P300 amplitude in risk allele carriers (O'Donoghue et al, 2014;Del Re et al, 2014).…”

“…The ANOVA on P3b amplitude showed no effect of GENOTYPE (F 1,89 = 1.9, p = .17, Gη 2 = .03, cf. O'Donoghue et al, 2014;Del Re et al, 2014), or any interactions including GENOTYPE (GENOTYPE*LOAD and GENOTYPE*LOCKING ps N .3, GENOTYPE*LOAD*LOCKING: F 2,178 = 2.2, p = .11, Gη 2 b .01). The ANCOVA, testing SDLat while controlling for amplitude, remained significant for GENOTYPE (F 1,89 = 5.8, p = .02, Gη 2 = .04), suggesting that our findings were not secondary to group differences in amplitude, and thus unlikely to be an artefact of different signal-to-noise ratio in the two groups.…”

Association between variants of zinc finger genes and psychiatric disorders: Systematic review and meta-analysis

“…Walters et al also found that schizophrenia patients who carried the rs1344706 risk allele performed better on working memory and episodic memory tasks. Recent studies showed that the rs1344706 T-allele was related to an increase in novel P300b amplitude, which is lower in patients than in controls (Del Re et al, 2014;O'Donoghue et al, 2014). This positive dose effect of the T-allele was also found with regard to attention, memory, language-relevant processes, and processing speed (Balog et al, 2011;Becker et al, 2012;Cummings et al, 2010;Walters et al, 2010), indicating that this risk allele may exert a protective effect on cognitive performance in schizophrenia.…”

Consensus paper of the WFSBP Task Force on Biological Markers: Criteria for biomarkers and endophenotypes of schizophrenia part II: Cognition, neuroimaging and genetics

“…COMT has been associated with amplitude (Gallinat et al 2003;Golimbet et al 2006) and NRG1 with latency (Kang et al 2012) and a significant association was reported between the P300 amplitude elicited by novel sounds (P3b component) and ZNF804A (Del Re et al 2014). …”