DTNBP1 genotype influences cognitive decline in schizophrenia
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.
References (17)
- et al.
Association of the DTNBP1 locus with schizophrenia in a U.S. population
Am. J. Hum. Genet.
(2004) - et al.
Genetic risk of neuropsychological impairment in schizophrenia: a study of monozygotic twins discordant and concordant for the disorder
Schizophr. Res.
(1995) - et al.
Intelligence quotient and neuropsychological profiles in patients with schizophrenia and in normal volunteers
Biol. Psychiatry
(2001) - et al.
Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia
Am. J. Hum. Genet.
(2002) - et al.
Cognitive development in schizophrenia: follow-back from the first episode
J. Clin. Exp. Neuropsychol.
(2006) - et al.
Genetic variation in DTNBP1 influences general cognitive ability
Hum. Mol. Genet.
(2006) - et al.
Neurocognition as a stable endophenotype in bipolar disorder and schizophrenia
JNMD
(2006) - et al.
Longitudinal assessment of premorbid cognitive functioning in patients with schizophrenia through examination of standardized scholastic test performance
Am. J. Psychiatry
(2002)
Cited by (105)
Abnormalities in the copper transporter CTR1 in postmortem hippocampus in schizophrenia: A subregion and laminar analysis
2021, Schizophrenia ResearchCitation Excerpt :DTNBP1 is considered by many (Bray et al., 2005; Marshall et al., 2017; Norton et al., 2006; Pae et al., 2008; Riley et al., 2009; Straub et al., 2002; Voisey et al., 2010; Zatz et al., 1993), but not all (Farrell et al., 2015; Mutsuddi et al., 2006; Schizophrenia Working Group, 2014) to be a susceptibility gene for schizophrenia. DTNBP1 allelic variability is associated with cognitive abnormalities in patients with first-episode psychosis (Varela-Gomez et al., 2015), and influences the severity of cognitive decline in schizophrenia (Burdick et al., 2007). Genetic variations that reduce dysbindin-1 expression can identify in which subjects (both humans and mice) antipsychotic drugs will likely improve cognitive impairments (Scheggia et al., 2018).
Deviation from expected cognitive ability across psychotic disorders
2018, Schizophrenia ResearchCitation Excerpt :The reduced familiality of decline from expectation in comparison to the familiality for the raw BACS composite scores (Hill et al., 2013) suggests that severe cognitive decline may be more related to the presence of psychotic illness than familial genetic factors, though the possibility of a highly nonlinear effect of incremental levels of risk genes on cognition remains a possibility. Genetic factors are well known to account for level of cognitive ability (Lyons et al., 2009); (Plomin and Craig, 1997; Haworth et al., 2010) and increased risk for intellectual decline (Burdick et al., 2007). The present findings of lower familiality estimates for deviation from expected cognitive ability against a background of strong heritability for BACS performance suggests that factors related to the presence of psychotic illness rather than shared familial factors are the primary cause of decline from cognitive expectation.
A review of molecular genetic studies of neurocognitive deficits in schizophrenia
2017, Neuroscience and Biobehavioral ReviewsCitation Excerpt :Four studies examined the effect of this gene in cognitive deficits of schizophrenia. Burdick et al. (2007) first demonstrated an association between a schizophrenia risk haplotype of DTNBP1 (rs909706-rs1018381-rs2619522-rs760761-rs2619528-rs1011313), CTCTAC, and greater decline in IQ in 183 schizophrenia/schizoaffective disorder patients. Baek et al. (2012) later reported a significant association between DTNBP1 rs760761 and rs1018381 and the attention/vigilance domain when comparing schizophrenia patients to controls.