Relationship Between a High-Risk Haplotype in the DTNBP1 (Dysbindin) Gene and Clinical Features of Schizophrenia

Abstract

Objective: The purpose of this study was to determine whether a haplotype in the dystrobrevin binding protein 1 (DTNBP1) gene previously associated with schizophrenia not only increases the susceptibility to psychotic illness but also to a more or less clinically specific form of psychotic illness. Method:In the Irish Study of High-Density Schizophrenia Families, subjects with psychotic illness (N=755) were given lifetime ratings of clinical features according to the Operational Criteria Checklist for Psychotic Illness. Exploratory and confirmatory factor analyses were used to extract five factors-hallucinations, delusions, negative, manic, and depressive symptoms-and to create factor-derived scores. The family-based transmission disequilibrium test operationalized in the program TRANSMIT was used to determine whether a high-risk haplotype in the DTNBP1 gene was overtransmitted to subjects in the upper 20th and 40th percentiles for each factor score. These results were compared to baseline overtransmission by examining the empirical distribution of chi-square statistics in groups of 5,000 replicates in which 20% and 40% of ill subjects were randomly selected. This analysis was done for both narrow and broad definitions of psychotic illness.Results: Subjects in the upper 40th percentile for the negative symptom factorin both the narrowly (p=0.004) and broadly (p=0.01) defined illness groupswere more likely to inherit the high-risk haplotype than would be expected by chance. No other significant relationships between clinical features and high-risk haplotype transmission were observed. Conclusions:The etiologically relevant variation in DTNBP1, which is in presumptive linkage disequilibrium with the highrisk haplotype, may predispose individuals to a form of psychotic illness associated with high levels of negative symptoms. This finding supports previous evidence suggesting that genetic factors influence the clinical heterogeneity of schizophrenia.

AKT1 Is Associated with Schizophrenia Across Multiple Symptom Dimensions in the Irish Study of High Density Schizophrenia Families

“…Along with shared environment, a major phenotype modifier is genetic, specific susceptibility alleles/haplotypes conferring liability to particular clinical subtypes (37,50). The significant under-transmission in our study of the Emamian et al risk haplotype across all OPCRIT symptom dimensions may indicate an effect on risk for psychosis unspecific to symptom factors.…”

“…This may be consistent with the strongest associations being at broader diagnostic categories, which include individuals with mood disorders. Using this approach at other schizophrenia risk loci, associations were identified with 1-2 symptom factors (37,51). Prior AKT1/schizophrenia associations in Caucasian samples (6,12) are with core schizophrenia or schizoaffective disorder (our D2 category).…”

“…From factor analysis of OPCRIT item lifetime ratings for ISHDSF subjects, five factors were extracted and used to derive scales; negative symptoms, delusions, hallucinations, mania and depression (37). For each scale, patients were divided into high and low-scoring categories to perform a family-based association test appropriate for our sample and design (38).…”

Early Visual Processing Deficits in Dysbindin-Associated Schizophrenia

“…The mean t (24) .488, p .63]. The mean correct rejection rate (to nontarget animals) for nonrisk subjects was .953 and .965 for risk subjects.…”

Variance in neurocognitive performance is associated with dysbindin-1 in schizophrenia: A preliminary study

“…This association has been strongest for patients with a preponderance of negative symptoms, and indeed negative symptoms have been found to correlate with performance deficits on measures of a variety of higher cognitive functions, including working memory (Donohoe et al, 2006a;Donohoe, Corvin, & Robertson, 2006;Donohoe & Robertson, 2003). It is therefore very interesting to note that the other main phenotype with which dysbindin has been associated is negative symptom severity (Derosse et al, 2006;Fanous et al, 2005). One interpretation of these data is that the Dysbindin risk haplotype may be contributing to the delineation of a subtype of schizophrenia characterised by a deficit syndrome (see also Gornick et al's (2005) study on dysbindin and poor pre-morbid adjustment).…”