Evaluation of a Susceptibility Gene for Schizophrenia: Genotype Based Meta-Analysis of RGS4 Polymorphisms from Thirteen Independent Samples

Talkowski, Michael E.; Seltman, Howard; Bassett, Anne S.; Brzustowicz, Linda M.; Chen, Xiangning; Chowdari, Kodavali V.; Collier, David; Cordeiro, Quirino; Corvin, Aiden; Deshpande, Smita N.; Egan, Michael; Gill, Michael; Kendler, Kenneth S.; Kirov, George; Heston, Leonard L.; Levitt, Pat; Lewis, David A.; Li, Tao; Mirnics, Károly; Morris, Derek W.; Norton, Nadine; O'Donovan, Michael Conlon; Richard, Christian; Semwal, Prachi; Sobell, Janet L.; Clair, David St; Straub, Richard E.; Thelma, B.K.; Vallada, Homero; Weinberger, Daniel R.; Williams, Nigel; Wood, Joel; Zhang, Feng; Devlin, Bernie; Nimgaonkar, Vishwajit L.

doi:10.1016/j.biopsych.2006.02.015

Cited by 91 publications

(61 citation statements)

References 60 publications

(54 reference statements)

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“…The variants in the 5′ region of RGS4 have not been analyzed yet for regulatory functions, and additional experiments will be required to identify the functional variants marked by association of the genotyped SNPs. However, the difference in baseline PANSS total score among RGS4 markers in the 5′ region of the gene may be consistent with the hypothesis that differential regulation of RGS4 contributes to the severity of schizophrenia symptoms (30). The different treatment responses among RGS4 genotypes, based on changes in PANSS scores and time to discontinuation of treatment, is consistent with our working hypothesis that (a) the pharmacologic actions of antipsychotic treatments could be influenced by RGS4 expression levels; and (b) certain RGS4 genotypes may be useful for predicting the efficacy of a particular treatment regimen in specific, ethnically defined patient populations.…”

Section: Discussionsupporting

confidence: 82%

“…Further, while the same single nucleotide polymorphisms (SNPs) in the 5′ region provide the strongest signal in association studies, the specific haplotypes have not been consistent across sample populations, which can be a hallmark of a false positive finding. However, a recent meta-analysis of more than 13,000 samples (30) evidenced additional support for the association of two common RGS4 haplotypes with schizophrenia in the presence of etiological heterogeneity.…”

Section: Introductionmentioning

confidence: 99%

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Ethnic Stratification of the Association of RGS4 Variants with Antipsychotic Treatment Response in Schizophrenia

Campbell

Ebert

Skelly

et al. 2008

Biological Psychiatry

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Background-Genetic association studies, including a large meta-analysis, report association of Regulator of G Protein Signaling 4 (RGS4) with schizophrenia in the context of heterogeneity. The central role of RGS4 in regulating signaling via Gi/o coupled neurotransmitter receptors led us to hypothesize that there may be RGS4 genotypes predictive of specific disease phenotypes and antipsychotic treatment responses.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Ethnic Stratification of the Association of RGS4 Variants with Antipsychotic Treatment Response in Schizophrenia

Campbell

Ebert

Skelly

et al. 2008

Biological Psychiatry

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“…However, the fact that there is such high LD within this narrow 5Ј untranslated region suggests that we may use rs951436 as a surrogate for other linked SNPs with previous positive associations to schizophrenia and that similar results to those seen here could reasonably be expected by testing these SNPs. Importantly, testing only rs951436, the most consistently associated variant across studies and the most significant association in a recent meta-analysis (Talkowski et al, 2006), circumvents the multiple comparisons issue that would apply in testing all variants within the region of high LD in the 5Ј upstream region of this gene.…”

Section: Limitationsmentioning

confidence: 99%

“…This same group found that genotype at their SNP 4 (rs951436) was associated with reduced DLPFC volume in first-episode schizophrenic patients and in healthy subjects (Prasad et al, 2004). A recent meta-analysis of published and unpublished data from multiple research centers (including our own schizophrenia genetics program) suggests that RGS4 is a weak susceptibility gene for schizophrenia, with the strongest association to rs951436, although the results are not conclusive (Talkowski et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Allelic Variation inRGS4Impacts Functional and Structural Connectivity in the Human Brain

Buckholtz¹,

Meyer‐Lindenberg²,

Honea³

et al. 2007

J. Neurosci.

100

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Regulator of G-protein signaling 4 (RGS4) modulates postsynaptic signal transduction by affecting the kinetics of G␣-GTP binding. Linkage, association, and postmortem studies have implicated the gene encoding RGS4 (RGS4) as a schizophrenia susceptibility factor. Using a multimodal neuroimaging approach, we demonstrate that genetic variation in RGS4 is associated with functional activation and connectivity during working memory in the absence of overt behavioral differences, with regional gray and white matter volume and with gray matter structural connectivity in healthy human subjects. Specifically, variation at one RGS4 single nucleotide polymorphism that has been associated previously with psychosis (rs951436) impacts frontoparietal and frontotemporal blood oxygenation level-dependent response and network coupling during working memory and results in regionally specific reductions in gray and white matter structural volume in individuals carrying the A allele. These findings suggest mechanisms in brain for the association of RGS4 with risk for psychiatric illness.

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“…[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. Each of the susceptibility genes identified thus far in these regions, when analyzed alone, accounts for only a small increase in risk, usually less than twofold.…”

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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Evaluation of a Susceptibility Gene for Schizophrenia: Genotype Based Meta-Analysis of RGS4 Polymorphisms from Thirteen Independent Samples

Cited by 91 publications

References 60 publications

Ethnic Stratification of the Association of RGS4 Variants with Antipsychotic Treatment Response in Schizophrenia

Ethnic Stratification of the Association of RGS4 Variants with Antipsychotic Treatment Response in Schizophrenia

Allelic Variation inRGS4Impacts Functional and Structural Connectivity in the Human Brain

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

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