Abstract
The rs1344706 polymorphism in ZNF804A is robustly associated with schizophrenia and schizophrenia is, in turn, associated with abnormal non-rapid eye movement (NREM) sleep neurophysiology. To examine whether rs1344706 is associated with intermediate neurophysiological traits in the absence of disease, we assessed the relationship between genotype, sleep neurophysiology, and sleep-dependent memory consolidation in healthy participants. We recruited healthy adult males with no history of psychiatric disorder from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. Participants were homozygous for either the schizophrenia-associated ‘A’ allele (N = 22) or the alternative ‘C’ allele (N = 18) at rs1344706. Actigraphy, polysomnography (PSG) and a motor sequence task (MST) were used to characterize daily activity patterns, sleep neurophysiology and sleep-dependent memory consolidation. Average MST learning and sleep-dependent performance improvements were similar across genotype groups, albeit more variable in the AA group. During sleep after learning, CC participants showed increased slow-wave (SW) and spindle amplitudes, plus augmented coupling of SW activity across recording electrodes. SW and spindles in those with the AA genotype were insensitive to learning, whilst SW coherence decreased following MST training. Accordingly, NREM neurophysiology robustly predicted the degree of overnight motor memory consolidation in CC carriers, but not in AA carriers. We describe evidence that rs1344706 polymorphism in ZNF804A is associated with changes in the coordinated neural network activity that supports offline information processing during sleep in a healthy population. These findings highlight the utility of sleep neurophysiology in mapping the impacts of schizophrenia-associated common genetic variants on neural circuit oscillations and function.
Highlights
Schizophrenia (SZ) is a debilitating psychiatric disorder with a lifetime prevalence of up to 4% 1
1) all participants showed normal wake/sleep rhythms and sleep architecture; 2) we observed greater variance in learning and sleep-dependent memory consolidation following a motor task in AA participants; 3) we detected genotype- and learningdependent effects on SW and fast spindle amplitudes, with the AA group showing normal SW and spindle densities, but attenuated changes in SW and spindle amplitudes after learning; 4) the AA group failed to exhibit the learning-dependent increase in SW coherence evident in the CC genotype group; 5) metrics of coordinated network activity during non-rapid eye movement (NREM) sleep were robust predictors of sleep-dependent memory consolidation in CC participants, but unable to predict behavior in the AA group associated with higher genetic liability for schizophrenia
Motor memory consolidation Using an motor sequence task (MST), performance in which has previously shown to be impaired in SZ patients, we found evidence for greater variability in overnight improvement and other variables derived from MST in those with the AA genotype at rs1344706, suggesting that rs1344706 may associate with subtle changes in motor learning and consolidation
Summary
Schizophrenia (SZ) is a debilitating psychiatric disorder with a lifetime prevalence of up to 4% 1. The single nucleotide polymorphism (SNP) rs1344706 within the second intron of ZNF804A was the first SNP to show genome-wide significant association for psychosis in both bipolar disorder and SZ 6. This finding has been replicated in subsequent genome wide association studies (GWAS) 4,7–9 including a fine-mapping study which confirmed an OR for SZ of 1.10 [1.07–1.14] 10. Though the sole contributions of ZNF804A polymorphisms to psychiatric risk are small, there is rationale and precedent for mapping associations between ZNF804A variants and brain physiology and function. Slow oscillations and their coordination with spindles have been implicated in deficits in sleep-dependent memory consolidation in patients [41,42,43]. Altered NREM oscillations are evident in first-degree relatives 44, are not driven purely by diagnosis or medication
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