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.
Highlights
The genetic contribution to developing SZ is relatively high, with heritability estimates of 81% by meta-analysis of twin studies[1] and 64% by a large family-based study.[2]
Several event-related potential (ERP) are considered to be intermediate phenotypes of SZ, with amplitude or latency abnormalities observed in affected individuals and unaffected relatives.[15,16,17]
The sample (N = 143) utilized in this study consisted of a total of 68 cases, including 27 individuals with clinical high risk (CHR) or putatively prodromal symptoms, 25 persons within the first episode of schizophrenia (FESZ), and 16 people with chronic schizophrenia (CSZ), as well as 75 healthy control participants
Summary
The genetic contribution to developing SZ is relatively high, with heritability estimates of 81% by meta-analysis of twin studies[1] and 64% by a large family-based study.[2]. Received 4 July 2013; revised 30 October 2013; accepted 3 November 2013 processing and habituation to the stimulus,[27] notably the dorsolateral prefrontal cortex and the hippocampus.[18,28,29,30] Menon and Uddin[31] have proposed a model whereby the anterior cingulate response to a novel stimulus is preceded by amplification of the salient event by the insula Both brain regions define the ‘salience network’ that is important in dynamic switching between centralexecutive and default mode networks in processes mediating detection of salient events and capturing of attention.[32]. We explored the relationship between the novel P300b component and experimental neurocognitive measures of auditory attention and working memory as a means of linking novel P300 to cognitive non-target novel stimuli (300–320 ms duration, 75 dB sound pressure level) consisting of six different complex environmental sounds (for example, dog bark, door slamming).[18] The inter-stimulus interval was 976 ms (onsetto-onset). Ag/AgCl electrodes in an electrode cap at 64 standard scalp sites (DC-100 Hz bandpass filter, 512 Hz digitization rate) with DC offsets kept below
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