Cannon, T.D., Hennah, W., van Erp, T.G., Thompson, P.M., Lonnqvist, J., Huttunen, M. et al. Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory. Arch. Gen. Psychiatry 62, 1205-1213
Chromosome 1q42 is among several genomic regions showing replicated evidence of linkage with schizophrenia, but the specific susceptibility mechanisms underlying this relationship remain to be identified.
To examine a series of haplotype blocks of single-nucleotide polymorphic markers from a segment of 1q42 spanning the disrupted-in-schizophrenia 1 (DISC1) and translin-associated factor X (TRAX) genes for association with schizophrenia and several endophenotypic traits thought to be involved in disease pathogenesis.
Population-based twin cohort study.
Two hundred thirty-six subjects, consisting of 7 twin pairs concordant for schizophrenia (6 monozygotic [MZ] and 1 dizygotic [DZ]), 52 pairs discordant for schizophrenia (20 MZ and 32 DZ), and 59 demographically balanced normal pairs (28 MZ and 31 DZ), were drawn from a twin cohort consisting of all of the same-sex twins born in Finland from 1940 through 1957.
Psychiatric diagnosis, performance on neurocognitive tests of short- and long-term memory, and gray matter volume measurements taken from high-resolution magnetic resonance images.
A common haplotype incorporating 3 single-nucleotide polymorphic markers near the translocation break point of DISC1 (odds ratio, 2.6 [P = .02]) and a rare haplotype incorporating 4 markers from the DISC1 and TRAX genes (odds ratio, 13.0 [P = .001]) were significantly overrepresented among individuals with schizophrenia. These haplotypes were also associated with several quantitative endophenotypic traits previously observed to covary with schizophrenia and genetic liability to schizophrenia, including impairments in short- and long-term memory functioning and reduced gray matter density in the prefrontal cortex, as demonstrated using a population-based brain atlas method, with a trend toward association with reduced hippocampal volume.
Specific alleles of the DISC1 and TRAX genes on 1q42 appear to contribute to genetic risk for schizophrenia through disruptive effects on the structure and function of the prefrontal cortex, medial temporal lobe, and other brain regions. These effects are consistent with their production of proteins that play roles in neuritic outgrowth, neuronal migration, synaptogenesis, and glutamatergic neurotransmission.
"During the last decade, the study of the relation between DISC1 and different schizophrenia endophenotypes (e.g., brain structure and function, cognitive abnormalities), has provided evidence of association between variations in several DISC1 polymorphisms and brain structure, altered brain function and impaired cognitive performance, both in schizophrenic patients and in healthy subjects.4,5,15,16,17,18,19,20,21,22 However, few studies have examined the relationship between this gene and the clinical presentation in schizophrenia.11,23,24,25 "
[Show abstract][Hide abstract] ABSTRACT: Objective
DISC1 gene is one of the main candidate genes for schizophrenia since it has been associated to the illness in several populations. Moreover, variations in several DISC1 polymorphisms, and in particular Ser704Cys SNP, have been associated in schizophrenic patients to structural and functional modifications in two brain areas (pre-frontal cortex and hippocampus) that play a central role in the genesis of psychotic symptoms. This study tested the association between Ser704Cys DISC1 polymorphism and the clinical onset of psychosis.
Two hundred and thirteen Caucasian drug-naive patients experiencing a first episode of non-affective psychosis were genotyped for rs821616 (Ser704Cys) SNP of the DISC1 gene. The clinical severity of the illness was assessed using SAPS and SANS scales. Other clinical and socio-demographic variables were recorded to rule out possible confounding effects.
Patients homozygous for the Ser allele of the Ser704Cys DISC1 SNP had significantly (p<0.05) higher rates at the positive symptoms dimension (SAPS-SANS scales) and hallucinations item, compared to Cys carriers.
DISC1 gene variations may modulate the clinical severity of the psychosis at the onset of the disorder.
"positive cells per 0 . 04 mm 3 AE SEM of three animals per genotype . ( H – K ) In situ hybridization of GAD67 mRNA in sagittal WT and DBZ KO mouse brain sections . Expression of mRNAs for GAD67 was not altered in the prefrontal ( H and I ) and visual cortices ( J and K ) of DBZ KO mice . Scale bar , 200 mm . syndrome ( Blackwood and Muir , 2004 ; Cannon et al . , 2005 ; Kilpinen et al . , 2008 ; Sprooten et al . , 2011 ; Szeszko et al . , 2008 ) . Although DBZ interacts with DISC1 , to date only a few genetic analyses have suggested an association between DBZ gene and mental illness ( Liu et al . , 2003 ; Marcheco - Teruel et al . , 2006 ; Moens et al . , 2011 ; Segurado et al . , 2003 ) . Further ge"
[Show abstract][Hide abstract] ABSTRACT: Disrupted-in-schizophrenia 1 (DISC1)-binding zinc finger protein (DBZ) is a DISC1-interacting molecule and the interaction between DBZ and DISC1 is involved in neurite outgrowth in vitro. DBZ is highly expressed in brain, especially in the cortex. However, the physiological roles of DBZ in vivo have not been clarified. Here, we show that development of basket cells, a morphologically defined class of parvalbumin (PV)-containing interneurons, is disturbed in DBZ knockout (KO) mice. DBZ mRNA was highly expressed in the ventral area of the subventricular zone of the medial ganglionic eminence, where PV-containing cortical interneurons were generated, at embryonic 14.5 days (E14.5). Although the expression level for PV and the number of PV-containing interneurons were not altered in the cortices of DBZ KO mice, basket cells were less branched and had shorter processes in the somatosensory cortices of DBZ KO mice compared with those in the cortices of WT mice. Furthermore, in the somatosensory cortices of DBZ KO mice, the level of mRNAs for the gamma-aminobutyric acid-synthesizing enzymes GAD67 was decreased. These findings show that DBZ is involved in the morphogenesis of basket cells.
Journal of chemical neuroanatomy 08/2013; 53. DOI:10.1016/j.jchemneu.2013.07.002 · 1.50 Impact Factor
"Risk allele ( A ) of SNP rs821597 exhibited higher GM density in regional left parahippocampal gyrus in schizophrenia patients , however GM density in this area was reduced in healthy controls . Interactions Cannon et al . ( 2005 )"
[Show abstract][Hide abstract] ABSTRACT: Disrupted-in-Schizophrenia 1 (DISC1) is a well researched candidate gene for schizophrenia and affective disorders with a range of functions relating to neurodevelopment. Several human brain imaging studies investigating correlations between common and rare variants in DISC1 and brain structure and function have shown conflicting results. A meta-analysis of case/control data showed no association between schizophrenia and any common SNP in DISC1. Therefore it is timely to review the literature to plan the direction of future studies.
Schizophrenia Research 04/2013; DOI:10.1016/j.schres.2013.03.015 · 3.92 Impact Factor
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