Genetic association of single nucleotide polymorphisms in dystrobrevin binding protein 1 gene with schizophrenia in a Malaysian population

Abstract

Dystrobrevin binding protein 1 (DTNBP1) gene is pivotal in regulating the glutamatergic system. Genetic variants of the DTNBP1 affect cognition and thus may be particularly relevant to schizophrenia. We therefore evaluated the association of six single nucleotide polymorphisms (SNPs) with schizophrenia in a Malaysian population (171 cases; 171 controls). Associations between these six SNPs and schizophrenia were tested in two stages. Association signals with p < 0.05 and minor allele frequency > 0.05 in stage 1 were followed by genotyping the SNPs in a replication phase (stage 2). Genotyping was performed with sequenced specific primer (PCR-SSP) and restriction fragment length polymorphism (PCR-RFLP). In our sample, we found significant associations between rs2619522 (allele p = 0.002, OR = 1.902, 95%CI = 1.266 – 2.859; genotype p = 0.002) and rs2619528 (allele p = 0.008, OR = 1.606, 95%CI = 1.130 – 2.281; genotype p = 6.18 × 10−5) and schizophrenia. Given that these two SNPs may be associated with the pathophysiology of schizophrenia, further studies on the other DTNBP1 variants are warranted.

Dysregulation of Specialized Delay/Interference-Dependent Working Memory Following Loss of Dysbindin-1A in Schizophrenia-Related Phenotypes

“…The fact that these cognitive abnormalities were significant only in males may be consistent with reports noted earlier that some genetic variants in DTNBP1 modify risk for schizophrenia in males more than in females (Zuo et al, 2009;Voisey et al, 2010;Sacchetti et al, 2013;Tan et al, 2015). As also noted earlier, these variants are in non-coding regions of the DTBP1 gene, specifically introns 1, 3-4, and/or 7 close to exons encoding the NTR of dysbindin-1A (ie exons 1 and 3-5; Talbot et al, 2009).…”

“…Recent studies in patients with schizophrenia, the majority of whom were male, have likewise reported over-activity in a novel, human open-field paradigm, with disruption to habituation of initial exploratory activity (Perry et al, 2009(Perry et al, , 2010. Several DTNBP1 genetic variants (usually SNPs) in introns 1, 3, 4, and/or 7 are more closely associated with schizophrenia risk in males than in females, either increasing (Voisey et al, 2010;Tan et al, 2015) or decreasing (Zuo et al, 2009;Sacchetti et al, 2013) risk depending on the specific variants. If the genetic variants associated with increased risk for schizophrenia in males affect expression of exon 5 and thus dysbindin-1A, this could relate to the novelty-induced exploratory activity observed in male dys-1A − / − .…”

“…We report here that selective knockout of exon 5 in the DTNBP gene of C57Bl/6 J mice results in selective loss of dysbindin-1A without reduction of dysbindin-1C levels in the brain. We studied the behavioral phenotype in both male and female dysbindin-1A mutants given that sex influences schizophrenia incidence risk (greater in males: Aleman et al, 2003;McGrath et al, 2008;Abel et al, 2010;van der Werf et al, 2014) and peak age at onset (later in females: Häfner et al, 1998;van der Werf et al, 2014) and that schizophrenia risk associated with some genetic variants in DTNBP1 differs according to sex (Zuo et al, 2009;Voisey et al, 2010;Sacchetti et al, 2013;Tan et al, 2015). Accordingly, adult male and female heterozygous and homozygous mutants and WT mice were evaluated to determine phenotypic effects on a wide range of sensorimotor, schizophrenia-related and other behaviors.…”

Dissecting bipolar disorder complexity through epigenomic approach

“…Both in BD and in SZ patients, genotypic and haplotypic associations between the phenotype and DTNBP1 have been established. 102 , 103 , 104 It has been suggested that DTNBP1 may have a role in the AMPA receptor complexes, which binds glutamate as an agonist. 105 These findings suggest that genetic variants of the DTNBP1 gene confer to the susceptibility of disorder with psychotic features, whereas the actual risk of having a psychotic episode is bound to the methylation status of the DTNBP1 promoter, which interferes with the excitatory glutamate transmission system.…”

Population genetic structure analysis and forensic evaluation of Xinjiang Uigur ethnic group on genomic deletion and insertion polymorphisms

“…The short tandem repeats (STRs) are commonly used genetic makers in the field of forensic sciences, and single nucleotide polymorphisms (SNPs) are considered as alternative and supplementary markers to STRs (Gill 2001 ; Kidd et al 2005 ; Tan et al 2015 ; Ye et al 2014 ). SNPs can be captured in smaller amplicons than STRs without stutter in the profile.…”