Schizophrenia is associated with cognitive impairments [1, 2] as was already recognized by Kraepelin  who used the term "dementia praecox" to describe a chronic, deteriorating psychotic disorder characterized by progressive cognitive decline. To date, cognitive dysfunctions including deficiencies in attention, working memory, and executive functions are considered core features of the clinical schizophrenia phenotype, and are probably highly predictive for functional outcome [4, 5]. No single etiological substrate for schizophrenia and its associated cognitive profile has yet been identified, but common abnormalities include reductions in neuropil and size of neurons, and structural and functional abnormalities of prefrontal and temporal regions and the hippocampal formation . Also, altered glutamatergic neurotransmission has been implicated as a functional substrate for psychotic and cognitive symptoms in schizophrenia , in addition to the classical dopamine hypothesis . Evidence from genetic linkage and association, and twin studies points to a major contribution of genetic factors to schizophrenia etiology . Furthermore, since healthy family members of patients with schizophrenia show similar cognitive deficits, the cognitive profile associated with schizophrenia is probably highly heritable .
One of the key candidate genes to date is the dystrobrevin-binding protein 1 (DTNBP1, or dysbindin) gene. Not only have several genome scans reported linkage of chromosome 6p22–24 to schizophrenia [11–14], but also association has been reported between schizophrenia and a set of individual markers and haplotypes spanning the chromosomal region containing the DTNBP1 gene (6p22.3), a finding which has been replicated in several different populations [15–24]. Despite the large number of studies supporting DTBNP1 as a positional candidate gene for schizophrenia , functional variants have not yet been identified, nor have any pathophysiological mechanisms.
However, there is accumulating evidence that DTBNP1 may have a role in cognition. For example, one association study found a specific protective haplotype that was associated with higher educational achievement in patients with schizophrenia . The authors propose that this protective haplotype within DTNBP1 may modify schizophrenia risk by enhancing cognition. This hypothesis is supported by a recent genome scan for intelligence using a large sample of healthy sib-pairs, that revealed putative linkage on 6p25.3-6p22.3 , and by a linkage scan in schizophrenia patients reporting linkage at 6p24 to a neurocognitive deficit subtype of schizophrenia . In addition, post-mortem studies have shown that DTNBP1 expression is reduced in the hippocampus and prefrontal cortex of patients with schizophrenia, regions of the brain that are crucial for adequate cognitive functioning . DTNBP1 could also influence schizophrenia liability and cognition by modulating glutamatergic or dopaminergic neurotransmission: DTNBP1 is located in presynaptic glutamatergic neurons and is reduced in patients with schizophrenia ; furthermore, down-regulation of DTNBP1 may lead to hyperactivation of midbrain dopaminergic systems . Both the dopaminergic and the glutamatergic systems are key neurotransmitter systems for cognitive functioning [7, 31].
Recent data from two independent groups further support a role for DTNBP1 in cognition and schizophrenia susceptibility. Burdick et al  recently reported association between a DTNBP1 haplotype and general cognitive ability in patients with schizophrenia and in healthy controls. Patients with schizophrenia carrying a DTNBP1 risk haplotype previously identified by Funke , performed worse on a neurocognitive test battery including the Wechsler Adult Intelligence Test (WAIS) – Revised than patients without the risk haplotype. Likewise, healthy controls without the risk haplotype showed higher levels of general cognitive ability than those carrying the risk haplotype. Furthermore, a recent study by Donohoe et al  reported that patients with schizophrenia carrying a DTNBP1 risk haplotype showed impaired spatial working memory performance in comparison to patients without the risk haplotype. In addition to cognition, DTNBP1 has recently been associated with high levels of negative symptoms in patients with schizophrenia [34, 35]; these findings are relevant in this context since negative symptoms and cognitive dysfunction are highly correlated .
Given the evidence supporting DTNBP1 not only as a susceptibility gene for schizophrenia but also as a gene contributing to intellectual functioning, we hypothesized that variants in the DTNBP1 gene may contribute to the risk for schizophrenia by affecting cognitive abilities. To date, association between genetic variation in the DTNBP1 gene and intellectual functioning in unaffected relatives of patients with schizophrenia-spectrum disorders has not yet been studied. Therefore, we investigated association between SNPs in the DTNBP1 gene and IQ in patients with a first episode of schizophrenia or related psychotic disorder (first-episode psychosis, FEP), their unaffected siblings, and healthy controls.