NoteVariance in neurocognitive performance is associated with dysbindin-1 in schizophrenia: A preliminary study
Introduction
Deficits in cognitive performance are increasingly viewed as core to schizophrenia and highly predictive of functional outcome (Green, 1996, Heinrichs, 2005). The heritability of performance deficits on measures of executive function, vigilance, and declarative memory has been demonstrated in twin studies (Cannon et al., 2000, Goldberg et al., 1990) and in studies of first degree relatives (Egan et al., 2001, Faraone et al., 1995). This has lead to the suggestion that genetic liability for schizophrenia is at least partly mediated by deleterious effects on the brain regions associated with these cognitive functions, including pre-frontal and medial temporal lobe regions (Weinberger et al., 2001).
Recent reviews of schizophrenia genetics (Craddock, O’Donovan, & Owen, 2005) have highlighted the potential role of a number of candidate genes in conferring liability to the disorder. Among these, an association with dystrobrevin-binding protein 1 (dysbindin), a 40–50-kDa protein that is expressed in neurons throughout mouse and human brain, has been one of the most widely replicated findings, including in our own case-control sample (e.g. Schwab et al., 2003, Straub et al., 2002, Williams et al., 2004).
Although the biological significance of dysbindin remains unclear, a number of lines of evidence suggest that it may have a role in cognition. Firstly, using a cognitive phenotype, two studies have identified linkage to loci on chromosome 6p that are, respectively, overlapping with and adjacent to the dysbindin gene (Hallmayer et al., 2005, Posthuma et al., 2005). Secondly, two recent post-mortem studies have reported specific reductions in the expression of dysbindin in the hippocampal region (Talbot et al., 2004) and the dorsolateral pre-frontal cortex (Weickert et al., 2004) of deceased patients with schizophrenia. Talbot et al. (2004) and Numakawa et al. (2004) reported evidence that dysbindin is impacting on glutamate neurotransmission, which is associated with a number of cortical processes underpinning neurocognition, including hippocampal long term potentiation (Poo, 2001; Tyler, Alonso, Bramham, & Pozzo-Miller, 2002). Thirdly, dysbindin has recently been associated with variance in cognitive function in schizophrenia based on an index of general cognitive ability (Burdick et al., 2006).
We investigated the potential relationship between dysbindin haplotype carrier status and selected measures of neurocognitive impairments showing evidence of familiality in schizophrenia, namely episodic memory, working memory, and attentional control. We expected that if the risk for schizophrenia associated with dysbindin is at least partly mediated by its influence on neurocognitive function, then carriers of the risk haplotype will perform significantly worse on at least some neurocognitive measures.
Section snippets
Subjects
After approval was obtained from the relevant hospital ethics committees, we re-contacted patients from our original genetic sample (n = 359) who were still attending community psychiatric services in their local catchment area and who met our inclusion criteria (below). This sample was comprised entirely of patients of Irish origin (having Irish parents/grandparents). DSM-IV diagnosis was confirmed by a psychiatrist or psychiatric nurse trained to use the Structured Clinical Interview for DSM
Results
Mean scores on demographic and neurocognitive variables are presented for both risk haplotype and non-haplotype groups in Table 1. Demographic characteristics are described separately for each genotype group. While the two groups did not differ on the demographic and clinical variables presented, predictably, many cognitive variables correlated significantly with age and pre-morbid IQ. Age was significantly negatively correlated with verbal and spatial working memory, and CPT performance.
Discussion
Carriers of the Dysbindin risk haplotype performed more poorly than non-carriers on the CANTAB spatial working memory task. An association with spatial working memory is interesting for a number of reasons. Working memory has consistently been shown to be impaired in schizophrenia and to be at least partly under genetic influence, on the basis of both family studies (Glahn et al., 2003; Myles-Worsley & Park, 2002; Park, Holzman, & Goldman-Rakic, 1995) and molecular studies (e.g. the association
Acknowledgement
Our sincere thanks to patients and hospital staff who collaborated in this study. This work was generously supported by research grants from Science Foundation Ireland, The Higher Educational Authority (HEA) Ireland, and the Health Research Board Ireland.
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