Polymorphisms in the 13q33.2 gene G72/G30 are associated with childhood-onset schizophrenia and psychosis not otherwise specified

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

doi:10.1016/j.biopsych.2004.01.024

Cited by 137 publications

(92 citation statements)

References 26 publications

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“…12,13,19,20,[60][61][62] They are especially interesting as the same regions may encompass susceptibility genes for schizophrenia. [63][64][65][66][67][68][69][70] Park et al 71 made similar conclusions in a study of psychotic BD in which most areas of linkage overlapped with those reported in previous investigations of schizophrenia.…”

Section: Psychotic Symptoms In Bdsupporting

confidence: 71%

The phenotypes of bipolar disorder: relevance for genetic investigations

2005

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The search for susceptibility genes for bipolar disorder (BD) depends on appropriate definitions of the phenotype. In this paper, we review data on diagnosis and clinical features of BD that could be used in genetic studies to better characterize patients or to define homogeneous subgroups. Clinical symptoms, long-term course, comorbid conditions, and response to prophylactic treatment may define groups associated with more or less specific loci. One such group is characterized by symptoms of psychosis and linkage to 13q and 22q. A second group includes mainly bipolar II patients with comorbid panic disorder, rapid mood switching, and evidence of chromosome 18 linkage. A third group comprises typical BD with an episodic course and favourable response to lithium prophylaxis. Reproducibility of cognitive deficits across studies raises the possibility of using cognitive profiles as endophenotypes of BD, with deficits in verbal explicit memory and executive function commonly reported. Brain imaging provides a more ambiguous data set consistent with heterogeneity of the illness. Keywords: bipolar disorder; genetics; endophenotype; neurocognitive function; brain imaging Bipolar disorder (BD) has a genetic basis with heritability of at least 80%. 1 A number of studies have attempted to map the susceptibility loci giving evidence of linkage in multiple genomic regions. In particular, findings in 4p, 4q, 8q, 10p, 12q24, 13q, 18p, 18q, 21q, and 22q have been supported by more than one study. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] However, these studies have not identified any specific genes, and a recent metaanalysis of available genome scans showed no regions with a conclusive evidence of linkage. 20 The relatively slow progress of gene-mapping efforts is often explained by the 'complex' nature of the illness and of the genotype-phenotype relation. The complexity most likely includes heterogeneity, interactions of multiple loci, incomplete penetrance, as well as phenotypes resulting from environmental effects-either alone or in interaction with the genetic predisposition. The goal of psychiatric genetic research is identification of (heritable) variations in DNA sequence or function that influence behaviour or give rise to mental illness. By definition, in complex (multifactorial) traits, this link is not unique and specific. That is, a particular change in gene sequence does not necessarily lead to a specific behaviour, and similar behaviours (symptoms) may be due to distinct (sets of) genes. Moreover, we must consider the possibility that the path between the genotype and behaviour is not unidirectional. Emerging examples point not only to general effects of environment, for instance stress, on behaviour, but also to specific behaviours influencing gene function that can be transmitted onto the next generation. 21 No single method is considered clearly superior in identifying susceptibility genes for complex traits such as BD. Most researchers agree that a combination of strategies is most lik...

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Section: Psychotic Symptoms In Bdsupporting

confidence: 71%

The phenotypes of bipolar disorder: relevance for genetic investigations

2005

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“…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%

“…Nonetheless, we note that in our studies of three schizophrenia susceptibility genes to date, each gene demonstrates a very distinct pattern of association with the endophenotypic measures. 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%

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

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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.

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“…5,6 More importantly, genetic associations to genes in these linkage regions have been confirmed recently in multiple samples. [7][8][9] These genes include, among others, DISC1 on 1q, [10][11][12] DTNBP1 (dysbindin) on 6p, 13,14 NRG1 on 8p, 15 catechol-O-methyltransferase (COMT) on 22q, 16,17 DAOA (G72) on 13q 18,19 and RGS4 on 1q. [20][21][22] The linkage findings represented an important step, enabling targeted searches within defined regions of the genome.…”

Section: Introductionmentioning

confidence: 99%

Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression

et al. 2007

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Cortical GABAergic dysfunction has been implicated as a key component of the pathophysiology of schizophrenia and decreased expression of the gamma-aminobutyric acid (GABA) synthetic enzyme glutamic acid decarboxylase 67 (GAD 67 ), encoded by GAD1, is found in schizophrenic post-mortem brain. We report evidence of distorted transmission of single-nucleotide polymorphism (SNP) alleles in two independent schizophrenia family-based samples. In both samples, allelic association was dependent on the gender of the affected offspring, and in the Clinical Brain Disorders Branch/National Institute of Mental Health (CBDB/NIMH) sample it was also dependent on catechol-O-methyltransferase (COMT) Val158Met genotype. Quantitative transmission disequilibrium test analyses revealed that variation in GAD1 influenced multiple domains of cognition, including declarative memory, attention and working memory. A 5 0 flanking SNP affecting cognition in the families was also associated in unrelated healthy individuals with inefficient BOLD functional magnetic resonance imaging activation of dorsal prefrontal cortex (PFC) during a working memory task, a physiologic phenotype associated with schizophrenia and altered cortical inhibition. In addition, a SNP in the 5 0 untranslated (and predicted promoter) region that also influenced cognition was associated with decreased expression of GAD1 mRNA in the PFC of schizophrenic brain. Finally, we observed evidence of statistical epistasis between two SNPs in COMT and SNPs in GAD1, suggesting a potential biological synergism leading to increased risk. These coincident results implicate GAD1 in the etiology of schizophrenia and suggest that the mechanism involves altered cortical GABA inhibitory activity, perhaps modulated by dopaminergic function.

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Polymorphisms in the 13q33.2 gene G72/G30 are associated with childhood-onset schizophrenia and psychosis not otherwise specified

Cited by 137 publications

References 26 publications

The phenotypes of bipolar disorder: relevance for genetic investigations

The phenotypes of bipolar disorder: relevance for genetic investigations

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

Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression

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