Dysbindin‐1 gene contributes differentially to early‐ and adult‐onset forms of functional psychosis

Abstract

Dysbindin-1 is a relatively ubiquitous protein in the brain which is involved in the modulation of synaptic homeostasis. The dysbindin-1 gene (DTNBP1) has been associated with schizophrenia and bipolar disorder diagnoses. However, its contribution to the severity of the clinical and neurocognitive expression of these disorders remains controversial. We aimed to explore the association between DTNBP1 and the phenotypes which are more directly linked with the underlying biology, such as age at onset and neurocognitive impairment. The present family sample comprised 894 Caucasian individuals: 268 patients affected by functional psychosis [58% with illness onset before 18 years, mean age at onset (SD): 14.71 (2.10)], 483 parents and 143 siblings. Ten DTNBP1 single nucleotide polymorphisms were genotyped in all individuals and their transmission disequilibrium was tested in relation to: (i) the risk for psychosis; (ii) patients' age at onset; and (iii) familial neurocognitive performance (including IQ estimation and executive functioning). In early-onset families a 5-marker haplotype encompassing exons 2-4 and the surrounding introns was significantly over-transmitted to cases, while in adult-onset families two haplotypes corresponding to the region between introns 4 and 7 were over-transmitted to cases. Estimated IQ was associated with the rs760666 marker in the whole sample, whereas a significant association between executive functioning and the rs2619522 marker appeared in early-onset families. Our findings confirm the role of the dysbindin-1 gene in the risk for functional psychosis and show a differential haplotypic risk pattern in families with early as opposed to adult onset in the affected offspring.

The schizophrenia susceptibility gene DTNBP1 modulates AMPAR synaptic transmission and plasticity in the hippocampus of juvenile DBA/2J mice

“…Clinical features of schizophrenia include the positive symptoms of psychosis involving hallucinations and delusions. An association between a DTNBP1 gene variant and early-onset psychosis has been reported (Fatjo-Vilas et al, 2011). It was theorized that psychosis could be mediated by the inappropriate encoding of memories due to a mechanism involving enhanced synaptic transmission along an altered hippocampal excitatory pathway (Tamminga et al, 2010).…”

Association of the Hermansky–Pudlak syndrome type 4 (HPS4) gene variants with cognitive function in patients with schizophrenia and healthy subjects

“…Its function is uncertain because it is unlikely to affect the stability of HPS4 mRNA [17]. This is reminiscent of the relevant SNPs of the DTNBP1 gene, which are mostly intronic and have been significantly implicated in the executive function of healthy controls [30], in cases belonging to early-onset families with functional psychosis disorders [65], and in the spatial working memory in patients with schizophrenia [66]. This general aspect regarding the question as to why intronic SNPs are involved in cognitive function awaits further genetic study.…”

Classical Neurotransmitters and Neuropeptides Involved in Schizophrenia: How to Improve the Therapeutic Effect of the Antipsychotic Drugs

“…It has been reported that the haplotype of the dysbindin-1 gene was correlated with the form and severity of the psychosis [44]. Haplotypes of the dysbindin-1 gene are linked to glutaminergic dysfunctions in the hippocampal formation [43].…”