DTNBP1 genotype influences cognitive decline in schizophrenia

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Abstract

Objective

Intellectual decline is common in schizophrenia and predicts functional outcome. While many patients undergo intellectual decline that typically predates the onset of symptoms, few studies have investigated the underlying mechanism through which this occurs. The current study assessed the relationship between intellectual decline in schizophrenia and genetic variation in dysbindin-1 (DTNBP1).

Methods

We assessed cognitive decline in 183 Caucasian patients with schizophrenia using a proxy measure of premorbid IQ with which current general cognitive ability (g) was compared. We then tested for a relationship between the risk haplotype identified in previous work (CTCTAC) and intellectual decline.

Results

We found that carriers of the CTCTAC haplotype, demonstrated a significantly greater decline in IQ as compared with non-carriers (p = 0.05).

Conclusions

These data suggest that DTNBP1 influences the severity of intellectual decline in schizophrenia and may represent one underlying cause for heterogeneity in cognitive course.

Introduction

Substantial evidence suggests that a large proportion of patients with schizophrenia undergo a decline in intellectual functioning; however, there is considerable inter-individual variation in the degree of decline. Studies that have investigated intellectual functioning prior to the onset of schizophrenia and after illness onset, indicate that approximately 40–50% of patients are “deteriorating”, with an IQ decline of ≥ 10 points from premorbid IQ, while another 50% of patients do not demonstrate significant intellectual decline (Reichenberg et al., 2005, Weickert et al., 2000).

These data also suggest that many patients' intellectual functioning is impaired prior to the onset of illness (Reichenberg et al., 2005, Reichenberg et al., 2002, Fuller et al., 2002, Weickert et al., 2000). Reichenberg et al. (2005) recently reported that a majority of healthy adolescents who later manifest schizophrenia undergo a significant intellectual decline prior to the onset of psychotic symptoms. Intellectual decline, defined as a significantly lower than expected IQ at age 17, was associated with an increased risk for developing schizophrenia (Reichenberg et al., 2005). Subsequent to the initial episode (Bilder et al., 2006), cognitive performance, although impaired, appears to remain relatively stable in most patients, over short (2-year) and long (5-year and 10-year) term follow-up (Burdick et al., 2006a, Heaton et al., 2001). Given the early presence of decline and its stability over time, it is likely that genetic influences play a role in determining the severity of the decline, yet to date there have been no studies to identify specific genes that may differentiate these heterogeneous cognitive profiles.

Recently, however, a growing body of evidence suggests that the gene coding for dysbindin-1 (DTNBP1), initially identified by Straub et al. (2002), might influence intellectual decline in schizophrenia. First, DTNBP1 has been shown to influence risk for schizophrenia in several genetic linkage and association studies (for review see Norton et al., 2006), although not all studies have reported positive results. Second, post-mortem evidence suggests that DTNBP1 is expressed in regions of the brain that are critical to cognitive function and that its expression is reduced in hippocampus and prefrontal cortex in patients with schizophrenia (Weickert et al., 2004). Third, knockdown of endogenous dysbindin in primary cortical neuron culture results in decreased pre-synaptic protein expression and decreased release of glutamate (Numakawa et al., 2004), a key neurotransmitter thought to underlie cognitive dysfunction in schizophrenia. Finally, recent data from our group suggests that a schizophrenia risk haplotype in DTNBP1 (Funke et al., 2004) is associated with decreased general cognitive ability (g) in patients with schizophrenia and healthy volunteers (Burdick et al., 2006b). In this study group, we also have data on premorbid intellectual function and we have now assessed the effects of this 6-locus DTNBP1 risk haplotype (CTCTAC) on premorbid versus post-illness onset intelligence in 183 patients with schizophrenia to test the hypothesis that DTNBP1 influences intellectual decline in schizophrenia.

Section snippets

Experimental/materials and methods

The sample consisted of 183 unrelated Caucasian patients with schizophrenia or schizoaffective disorder who were administered a battery of standardized cognitive measures comprised of the Wechsler Adult Intelligence Test-Revised (WAIS-R)-Digit Span; Continuous Performance Test-Identical Pairs Version (CPT-I/P); California Verbal Learning Test (CVLT)-Abridged; Controlled Oral Word Association Test (COWAT), and Trail Making Tests A and B. Subjects were included if they were age 25 to 64 and had

Results

We found that patients with schizophrenia who carry the CTCTAC risk haplotype demonstrated a significantly greater decline in IQ (residual mean change = 13.5 ± 13.6) as compared with patients who do not carry the risk haplotype (residual mean change = 8.7 ± 12.4) (F = 4.00; df = 1, 182; p = 0.05; Fig. 1). Effect size calculations indicated that DTNBP1 genotype accounted for 2.2% of the variance in intellectual decline.

Haplotype groups did not differ on demographic or illness characteristics: Carrier vs.

Discussion

General intellectual decline is an important feature of schizophrenia and has been demonstrated to predict both functional outcome and variance in other more specific cognitive measures (Weickert et al., 2000). Here we show a significant effect of a DTNBP1 risk haplotype (CTCTAC) on IQ decline in patients with schizophrenia. CTCTAC carriers demonstrated a significantly greater decline in IQ (13.5 units) as compared with non-carriers (8.7 units), as measured via proxy measurements of premorbid

Acknowledgements

This work was supported by the Stanley Medical Research Institute.

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