ABSTRACT
DTNBP1 is one of the most established susceptibility genes for schizophrenia, and hippocampal volume reduction is one of the major neuropathological findings in this severe disorder. Consistent with these findings, the encoded protein dysbindin-1 has been shown to be diminished in glutamatergic hippocampal neurons in schizophrenic patients. The aim of this study was to investigate the effects of two single nucleotide polymorphisms of DTNBP1 on grey matter volumes in human subjects using voxel-based morphometry. Seventy-two subjects were included and genotyped with respect to two single nucleotide polymorphisms of DTNBP1 (rs2619522 and rs1018381). All participants underwent structural magnetic resonance imaging (MRI). MRI data were preprocessed and statistically analysed using standard procedures as implemented in SPM5 (Statistical Parametric Mapping), in particular the voxel-based morphometry (VBM) toolbox. We found significant effects of the DTNBP1 SNP rs2619522 bilaterally in the hippocampus as well as in the anterior middle frontal gyrus and the intraparietal cortex. Carriers of the G allele showed significantly higher grey matter volumes in these brain regions than T/T homozygotes. Compatible with previous findings on a role of dysbindin in hippocampal functions as well as in major psychoses, the present study provides first direct in vivo evidence that the DTNBP1 SNP rs2619522 is associated with variation of grey matter volumes bilaterally in the hippocampus.
Subject(s)
Carrier Proteins/genetics , Hippocampus/anatomy & histology , Polymorphism, Single Nucleotide/genetics , Prefrontal Cortex/anatomy & histology , Adolescent , Adult , Bipolar Disorder/genetics , Bipolar Disorder/pathology , Brain Mapping , DNA Mutational Analysis , Dysbindin , Dystrophin-Associated Proteins , Female , Genotype , Hippocampus/pathology , Humans , Image Processing, Computer-Assisted , Magnetic Resonance Imaging , Male , Middle Aged , Obsessive-Compulsive Disorder/genetics , Obsessive-Compulsive Disorder/pathology , Prefrontal Cortex/pathology , Retrospective Studies , Schizophrenia/genetics , Schizophrenia/pathology , Young AdultABSTRACT
DISC1 (Disrupted-In-Schizophrenia 1), one of the top candidate genes for schizophrenia, has been associated with a range of major mental illnesses over the last two decades. DISC1 is crucially involved in neurodevelopmental processes of the human brain. Several haplotypes and single nucleotide polymorphisms of DISC1 have been associated with changes of grey matter volumes in brain regions known to be altered in schizophrenia and other psychiatric disorders. The aim of the present study was to investigate the effects of two single nucleotide polymorphisms (SNPs) of DISC1 on grey matter volumes in human subjects using voxel-based morphometry (VBM). 114/113 participating subjects (psychiatric patients and healthy controls) were genotyped with respect to two at-risk SNPs of DISC1, rs6675281 and rs821616. All participants underwent structural magnetic resonance imaging (MRI). MRI data was statistically analyzed using voxel-based morphometry. We found significant alterations of grey matter volumes in prefrontal and temporal brain regions in association with rs6675281 and rs821616. These effects of DISC1 polymorphisms on brain morphology provide further support for an involvement of DISC1 in the neurobiology of major psychiatric disorders such as schizophrenia.
Subject(s)
Brain Mapping , Cerebral Cortex/anatomy & histology , Nerve Tissue Proteins/genetics , Polymorphism, Single Nucleotide/genetics , Adult , DNA Mutational Analysis , Female , Genotype , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Psychiatric Status Rating Scales , Schizophrenia/genetics , Schizophrenia/pathology , Young AdultABSTRACT
Two well-supported theories of schizophrenia pathogenesis are the neurotransmitter theory and the neurodevelopmental theory, suggesting, respectively, that dysregulation of neurotransmitter signaling and abnormal brain development are causative in this disease. The strongest evidence of neurotransmitter involvement are suggestions of abnormal dopamine signaling in the prefrontal cortex and one of the strongest indications of developmental abnormalities contributing to this disease is an inverse layering of the prefrontal cortex. These two theories of schizophrenia pathogenesis can be united by their involvement of the prefrontal cortex, where structural abnormalities could lead to neurochemical abnormalities. Accordingly, any gene expressed in the prefrontal cortex of developing brains is a functional candidate for schizophrenia. We have previously reported strong linkage to 15q15 (LOD = 3. 57; P = 2.6 x 10(-5)) in a collection of German multiplex families segregating the periodic catatonia subtype of schizophrenia in a nearly Mendelian fashion. A gene within our 15q15 linkage region, DLL4, is expressed in developing forebrain and produces a NOTCH4 ligand. Variants of NOTCH4 are associated with schizophrenia, thus DLL4 is both a functional as well as a positional candidate for schizophrenia. We screened this gene for mutations in three affected individuals and two unrelated controls and found two previously unreported SNPs, one non-synonymous polymorphism that changed an arganine to a histadine in Exon 7 and one synonymous polymorphism in exons. The non-synonymous SNP is a rare variant in that it was not found in 100 control chromosomes; however, it did not cosegregate with the disease in the extended family so it is not causative in this pedigree. It is unlikely that mutations in DLL4 are causative in this collection of families with linkage to 15q15.
