The Zinc Finger Protein 804A gene (ZNF804A) has been implicated in schizophrenia susceptibility by several genome-wide association studies. ZNF804A is brain expressed but of unknown function.
To investigate whether the identified risk allele at the disease-associated single nucleotide polymorphism rs1344706 is associated with variation in neuropsychological performance in patients and controls.
Comparison of cases and controls grouped according to ZNF804A genotype (AA vs AC vs CC) on selected measures of cognition in 2 independent samples.
Unrelated patients from general adult psychiatric inpatient and outpatient services and unrelated healthy participants from the general population were ascertained.
Patients with DSM-IV-diagnosed schizophrenia and healthy participants from independent samples of Irish (297 cases and 165 controls) and German (251 cases and 1472 controls) nationality.
In this 2-stage study, we tested for an association between ZNF804A rs1344706 and cognitive functions known to be impaired in schizophrenia (IQ, episodic memory, working memory, and attention) in an Irish discovery sample. We then tested significant results in a German replication sample.
In the Irish samples, the ZNF804A genotype was associated with differences in episodic and working memory in patients but not in controls. These findings replicated in the same direction in the German samples. Furthermore, in both samples, when patients with a lower IQ were excluded, the association between ZNF804A and schizophrenia strengthened.
In a disorder characterized by heterogeneity, a risk variant at ZNF804A seems to delineate a patient subgroup characterized by relatively spared cognitive ability. Further work is required to establish whether this represents a discrete molecular pathogenesis that differs from that of other patient groups and whether this also has consequences for nosologic classification, illness course, or treatment.
"It would be interesting to investigate whether rs1344706 carriers have altered ZNF804A expression selectively in the CA1 region of the hippocampus during adolescence, as our results suggest that there is a transient upregulation of Zfp804a at this neurodevelopmental stage. If there was dysregulation of Zfp804a in this region, at this stage, then it could potentially contribute to cognition impairment in individuals with schizophrenia (Walters et al., 2010). rs1344706 risk allele carriers have been shown to have larger hippocampal volumes than non-carriers (Donohoe et al., 2011), suggesting a specific effect on hippocampal structure. "
"The earlier work by Walters et al.  provided a thorough surveying of rs1344706 genotypic consequences in the context of neurocognitive performance. From their examination of ZNF804A on the effects of cognitive functions in an Irish case–control sample, the authors reported reliable associations of the risk SNP with aspects of verbal and spatial working memory which they replicated in a separate analysis of German subjects [Walters et al., 2010]. Contrary to the reports by Walters et al., Voineskos et al.  did not observe a significant association of rs1344706 in the context of working memory; however, they found that presence of the risk allele accompanies the reduced cortical thickness exhibited in multiple brain regions (e. g., anterior cingulated cortex, posterior cingulated cortex, and superior temporal gyrus) in their healthy adult samples. "
"Diagnosis was confirmed by trained psychiatrists using the Structured Clinical Interview for DSM-IV Axis I Diagnoses (SCID; First et al. 1995). Additional diagnostic and clinical information ascertained at time of interview, including symptom severity (SAPS/SANS; Andreasen 1984a,b) and medication dosage are detailed elsewhere (Walters et al. 2010). The healthy control sample was recruited on the basis of response to local media advertisements. "
[Show abstract][Hide abstract] ABSTRACT: The single nucleotide polymorphism rs10503253, located within the CUB and Sushi multiple domains-1 (CSMD1) gene on 8p23.2, was recently identified as genome wide significant for schizophrenia, but is of unknown function. We investigated the neurocognitive effects of this CSMD1 variant in vivo in patients and healthy participants using behavioral and imaging measures of brain structure and function. We compared carriers and non-carriers of the risk 'A' allele on measures of neuropsychological performance typically impaired in schizophrenia (General cognitive ability, episodic and working memory, and attentional control) in independent samples of Irish patients (n=387) and controls (n=171) and German patients (205) and controls (n=533). Across these groups, the risk 'A' allele at CSMD1 was associated with deleterious effects across a number of neurocognitive phenotypes. Specifically, the risk allele was associated with poorer performance on neuropsychological measures of general cognitive ability and memory function but not attentional control. These effects, while significant, were subtle, and varied between samples. Consistent with previous evidence suggesting that CSMD1 may be involved in brain mechanisms related to memory and learning, these data appear to reflect the deleterious effects of the identified 'A' risk allele on neurocognitive function, possibly as part of the mechanism by which CSMD1 is associated with schizophrenia risk.
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