[Show abstract][Hide abstract] ABSTRACT: The common variant rs1344706 within the zinc-finger protein gene ZNF804A has been strongly implicated in schizophrenia (SZ) susceptibility by a series of recent genetic association studies. Although associated with a pattern of altered neural connectivity, evidence that increased risk is mediated by an effect on cognitive deficits associated with the disorder has been equivocal. This study investigated whether the same ZNF804A risk allele was associated with variation in the P300 auditory-evoked response, a cognitively relevant putative endophenotype for SZ. We compared P300 responses in carriers and noncarriers of the ZNF804A risk allele genotype groups in Irish patients and controls (n=97). P300 response was observed to vary according to genotype in this sample, such that risk allele carriers showed relatively higher P300 response compared with noncarriers. This finding accords with behavioural data reported by our group and others. It is also consistent with the idea that ZNF804A may have an impact on cortical efficiency, reflected in the higher levels of activations required to achieve comparable behavioural accuracy on the task used.
[Show abstract][Hide abstract] ABSTRACT: The nitric oxide synthasase-1 gene (NOS1) has been implicated in mental disorders including schizophrenia and variation in cognition. The NOS1 variant rs6490121 identified in a genome wide association study of schizophrenia has recently been associated with variation in general intelligence and working memory in both patients and healthy participants. Whether this variant is also associated with variation in early sensory processing remains unclear.
We investigated differences in the P1 visual evoked potential in a high density EEG study of 54 healthy participants. Given both NOS1's association with cognition and recent evidence that cognitive performance and P1 response are correlated, we investigated whether NOS1's effect on P1 response was independent of its effects on cognition using CANTAB's spatial working memory (SWM) task.
We found that carriers of the previously identified risk "G" allele showed significantly lower P1 responses than non-carriers. We also found that while P1 response and SWM performance were correlated, NOS1 continued to explain a significant proportion of variation in P1 response even when its effects on cognition were accounted for.
The schizophrenia implicated NOS1 variants rs6490121 influences visual sensory processing as measured by the P1 response, either as part of the gene's pleiotropic effects on multiple aspects of brain function, or because of a primary influence on sensory processing that mediates the effects already seen in higher cognitive processes.
Human Brain Mapping 04/2011; 33(5):1202-11. · 6.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Archives of general psychiatry 07/2010; 67(7):692-700. · 12.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Human and animal studies have implicated the gene NOS1 in both cognition and schizophrenia susceptibility.
To investigate whether a potential schizophrenia risk single-nucleotide polymorphism (rs6490121) identified in a recent genome-wide association study negatively influences cognition in patients with schizophrenia and healthy control subjects.
A comparison of both cases and controls grouped according to NOS1 genotype (GG vs AG vs AA) on selected measures of cognition in 2 independent samples. We tested for association between NOS1 rs6490121 and cognitive functions known to be impaired in schizophrenia (IQ, episodic memory, working memory, and attentional control) in an Irish sample. We then sought to replicate the significant results in a German sample.
Unrelated patients from general adult psychiatric inpatient and outpatient services and unrelated healthy volunteers from the general population were ascertained.
Patients with DSM-IV-diagnosed schizophrenia and healthy control subjects from independent samples of Irish (cases, n = 349; controls, n = 230) and German (cases, n = 232; controls, n = 1344) nationality.
A main effect of NOS1 genotype on verbal IQ and working memory was observed in the Irish sample where the homozygous carriers of the schizophrenia risk G allele performed poorly compared with the other genotype groups. These findings were replicated in the German sample, again with the GG genotype carriers performing below other genotype groups. Post hoc analysis of additional IQ measures (full-scale and performance IQ) in the German sample revealed that NOS1 GG carriers underperformed on these measures also.
NOS1 is associated with clinically significant variation in cognition. Whether this is a mechanism by which schizophrenia risk is increased (eg, via an influence on cognitive reserve) is yet to be confirmed.
Archives of general psychiatry 10/2009; 66(10):1045-54. · 12.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Attributional style is defined as the pervasive tendency to explain the cause of social actions in terms of oneself, or others, or the context of the event. While the clinical correlates of this aspect of social cognition have been widely researched, its links with relationship style and neuropsychological performance, although hypothesised, have received less attention. This study investigated whether attributional style is predicted by variance in either relationship style or neuropsychological performance in schizophrenia. We assessed attributional style (using the Internal, Personal and Situational Attributions Questionnaire [IPSAQ]), relationship style (using Bartholomew and Horowitz's Relationship Questionnaire), and neuropsychological function (using the Wechsler Abbreviated Scale of Intelligence, the Wechsler Memory Test, and the Cambridge Automated Test Battery) in 73 stabilised outpatients with chronic schizophrenia and 78 controls matched for age and gender. 'Externalising bias' (attributing positive rather than negative events to oneself) was predicted by verbal ability in both patients and controls. 'Personalising bias' (attributing negative events to others rather than to situational factors) was predicted by higher secure relationship style ratings, but only in the patient group. This study highlights the importance of relationship style and neuropsychological performance for different aspects of attributional style in schizophrenia.
Psychiatry Research 10/2008; 161(1):19-27. · 2.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: An association between deficits in executive control, particularly inhibitory control, and more severe negative and disorganised symptoms of schizophrenia has been widely reported. The importance of more basic aspects of attention, often referred to as 'vigilant' or 'sustained' attention, to this relationship remains unclear. This study examined the contribution of sustained attention to symptom severity using the Sustained Attention to Response Task (SART) in 69 patients with schizophrenia. We found that negative and disorganised symptom severity scores were correlated with sustained attention, working memory, and psychomotor speed. The ability to sustain attention significantly predicted variance in negative symptom severity but not disorganised symptoms, which were instead predicted by working memory performance. These data suggest that this component of attention at least partly explains variance in negative symptoms.
Schizophrenia Research 10/2008; 107(2-3):319-23. · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Theory of mind deficits in schizophrenia have been parsed into mental state reasoning and mental state decoding components. We report that mental state decoding as measured by the 'Eyes task' better predicted social function than mental state reasoning as measured by the 'Hinting task' in 73 out-patients with chronic schizophrenia. Mental state decoding task performance also partly mediated the influence of basic neuropsychological performance on social function. We discuss these findings in terms of the accumulating evidence that mental state decoding has particular relevance for understanding deficits in social function in schizophrenia.
The British Journal of Psychiatry 08/2008; 193(1):77-8. · 6.61 Impact Factor