Dysbindin (DTNBP1, 6p22.3) is Associated with Childhood-Onset Psychosis and Endophenotypes Measured by the Premorbid Adjustment Scale (PAS)

Gornick, Michele C.; Addington, Anjené; Sporn, Alexandra; Gogtay, Nitin; Greenstein, Deanna; Lenane, Marge; Gochman, Peter; Ordóñez, Anna E.; Balkissoon, Rishi; Vakkalanka, Radhakrishna; Weinberger, Daniel R.; Rapoport, Judith L.; Straub, Richard E.

doi:10.1007/s10803-005-0028-3

Cited by 75 publications

(64 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is a intriguing finding that deserves follow-up, particularly in light of the fact that we had multiple volumetric scans on only 39 of our cases for analysis. Moreover, other genes that we studied (eg G72, DTNBP1) 40,41 did not show such an association, suggesting that this finding is not an artifact/confound under the diagnosis of COS. Finally, as we expected, there was no association observed between SNPs in the GAD2 locus, which encodes for GAD 65 .…”

Section: Discussionmentioning

confidence: 71%

“…Specifically, the G72 gene was associated with age of onset and scores on the Autism Screening Questionnaire, 40 while SNPs in the gene Dysbindin were associated with scores on the Premorbid Development Scale. 41 It is plausible that careful study of quantitative intermediate phenotypes in relationship to susceptibility genes for complex diseases such as schizophrenia can elucidate characteristic effects of each gene and how it may relate to the disease of interest.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD67), is associated with childhood-onset schizophrenia and cortical gray matter volume loss

Addington¹,

Gornick²,

et al. 2004

View full text Add to dashboard Cite

Postmortem brain studies have shown deficits in the cortical c-aminobutyric acid (GABA) system in schizophrenic individuals. Expression studies have shown a decrease in the major GABA-synthesizing enzyme (glutamic acid decarboxylase (GAD 67 ) mRNA levels in neurons in dorsolateral prefrontal cortex in schizophrenics relative to controls. In the present study, SNPs in and around the GAD1 gene, which encodes the protein GAD 67 , were tested on a rare, severely ill group of children and adolescents with childhood-onset schizophrenia (COS) (n ¼ 72), in a family-based association analysis. Compared to adult-onset samples, the COS sample has evidence for more salient familial, and perhaps genetic, risk factors for schizophrenia, as well as evidence for frontal cortical hypofunction, and greater decline in cortical gray matter volume on anatomic brain MRI scans during adolescence. We performed family-based TDT and haplotype association analyses of the clinical phenotype, as well as association analyses with endophenotypes using the QTDT program. Three adjacent SNPs in the 5 0 upstream region of GAD1 showed a positive pairwise association with illness in these families (P ¼ 0.022-0.057). Significant transmission distortion of 4-SNP haplotypes was also observed (P ¼ 0.003-0.008). Quantitative trait TDT analyses showed an intriguing association between several SNPs and increased rate of frontal gray matter loss. These observations, when taken together with the positive results reported recently in two independent adult-onset schizophrenia pedigree samples, suggest that the gene encoding GAD 67 may be a common risk factor for schizophrenia. Molecular Psychiatry (2005) 10, 581-588.

show abstract

Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD67), is associated with childhood-onset schizophrenia and cortical gray matter volume loss

Addington¹,

Gornick²,

et al. 2004

View full text Add to dashboard Cite

show abstract

“…It is notable that this relatively small, ethnically heterogeneous population could provide such a finding and supports other evidence that COS is genetically related to the more common adult-onset form of the disorder. [36][37][38] Further, the analysis of risk genotypes and neurodevelopmental trajectories throughout adolescence represents a unique endophenotype that could provide insight into the pathogenesis of specific genes in schizophrenia. Intriguingly, possession of an NRG1 risk allele had somewhat different effects on brain development trajectories of both gray and white matter in the COS patients as compared to healthy controls.…”

Section: Discussionmentioning

confidence: 99%

Neuregulin 1 (8p12) and childhood-onset schizophrenia: susceptibility haplotypes for diagnosis and brain developmental trajectories

Addington¹,

Gornick²,

Shaw³

et al. 2006

Mol Psychiatry

110

View full text Add to dashboard Cite

Childhood-onset schizophrenia (COS), defined as onset of psychosis by the age of 12, is a rare and malignant form of the illness, which may have more salient genetic influence. Since the initial report of association between neuregulin 1 (NRG1) and schizophrenia in 2002, numerous independent replications have been reported. In the current study, we genotyped 56 markers (54 single-nucleotide polymorphisms (SNPs) and two microsatellites) spanning the NRG1 locus on 78 COS patients and their parents. We used family-based association analysis for both diagnostic (extended transmission disequilibrium test) and quantitative phenotypes (quantitative transmission disequilibrium test) and mixed-model regression. Most subjects had prospective anatomic brain magnetic resonance imaging (MRI) scans at 2-year intervals. Further, we genotyped a sample of 165 healthy controls in the MRI study to examine genetic risk effects on normal brain development. Individual markers showed overtransmission of alleles to affecteds (P = 0.009-0.05). Further, several novel four-marker haplotypes demonstrated significant transmission distortion. There was no evidence of epistasis with SNPs in erbB4. The risk allele (0) at 420M9-1395 was associated with poorer premorbid social functioning. Further, possession of the risk allele was associated with different trajectories of change in lobar volumes. In the COS group, risk allele carriers had greater total gray and white matter volume in childhood and a steeper rate of subsequent decline in volume into adolescence. By contrast, in healthy children, possession of the risk allele was associated with different trajectories in gray matter only and was confined to frontotemporal regions, reflecting epistatic or other illness-specific effects mediating NRG1 influence on brain development in COS. This replication further documents the role of NRG1 in the abnormal brain development in schizophrenia. This is the first demonstration of a disease-specific pattern of gene action in schizophrenia.

show abstract

“…The expression of dysbindin is reduced in prefrontal cortex and hippocampus in schizophrenia [147]. Notably, the dysbindin genotype has been inversely associated with general cognitive ability and poor premorbid function in schizophrenia [148,149].…”

Section: Daaomentioning

confidence: 99%

Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

Lisman

Coyle

Green

et al. 2008

Trends in Neurosciences

896

811

View full text Add to dashboard Cite

Many risk genes interact synergistically to produce schizophrenia and many neurotransmitter interactions have been implicated. We have developed a circuit-based framework for understanding gene and neurotransmitter interactions. NMDAR hypofunction has been implicated in schizophrenia because NMDAR antagonists reproduce symptoms of the disease. One action of antagonists is to reduce the excitation of fast-spiking interneurons, resulting in disinhibition of pyramidal cells. Overactive pyramidal cells, notably those in the hippocampus, can drive a hyperdopaminergic state that produces psychosis. Additional aspects of interneuron function can be understood in this framework, as follows. (i) In animal models, NMDAR antagonists reduce parvalbumin and GAD67, as found in schizophrenia. These changes produce further disinhibition and can be viewed as the aberrant response of a homeostatic system having a faulty activity sensor (the NMDAR). (ii) Disinhibition decreases the power of gamma oscillation and might thereby produce negative and cognitive symptoms. (iii) Nicotine enhances the output of interneurons, and might thereby contribute to its therapeutic effect in schizophrenia.

show abstract

Dysbindin (DTNBP1, 6p22.3) is Associated with Childhood-Onset Psychosis and Endophenotypes Measured by the Premorbid Adjustment Scale (PAS)

Cited by 75 publications

References 39 publications

GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD67), is associated with childhood-onset schizophrenia and cortical gray matter volume loss

GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD67), is associated with childhood-onset schizophrenia and cortical gray matter volume loss

Neuregulin 1 (8p12) and childhood-onset schizophrenia: susceptibility haplotypes for diagnosis and brain developmental trajectories

Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

Contact Info

Product

Resources

About