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

Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
Biological Psychiatry (Impact Factor: 10.25). 08/2006; 60(2):152-62. DOI: 10.1016/j.biopsych.2006.02.015
Source: PubMed

ABSTRACT Associations between schizophrenia (SCZ) and polymorphisms at the regulator of G-protein signaling 4 (RGS4) gene have been reported (single nucleotide polymorphisms [SNPs] 1, 4, 7, and 18). Yet, similar to other SCZ candidate genes, studies have been inconsistent with respect to the associated alleles.
In an effort to resolve the role for RGS4 in SCZ susceptibility, we undertook a genotype-based meta-analysis using both published and unpublished family-based and case-control samples (total n = 13,807).
The family-based dataset consisted of 10 samples (2160 families). Significant associations with individual SNPs/haplotypes were not observed. In contrast, global analysis revealed significant transmission distortion (p = .0009). Specifically, analyses suggested overtransmission of two common haplotypes that account for the vast majority of all haplotypes. Separate analyses of 3486 cases and 3755 control samples (eight samples) detected a significant association with SNP 4 (p = .01). Individual haplotype analyses were not significant, but evaluation of test statistics from individual samples suggested significant associations.
Our collaborative meta-analysis represents one of the largest SCZ association studies to date. No individual risk factor arose from our analyses, but interpretation of these results is not straightforward. Our analyses suggest risk due to at least two common haplotypes in the presence of heterogeneity. Similar analysis for other putative susceptibility genes is warranted.

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Available from: Karoly Mirnics, Aug 01, 2015
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    • "This work includes research demonstrating the possible efficacy of the compound guanfacine in improving attention and working memory, a drug which inhibits one of the pathways activating HCN channels (Wang et al., 2007). Genetic variants DISC1, PDE4B, DGKH, and RGS4, each of which affect cAMP signaling, have risk modifying effects in mood disorders and schizophrenia (Thomson et al., 2005; Talkowski et al., 2006; Baum et al., 2007; Pickard et al., 2007). None to date show clear diagnostic specificity, although there is some evidence that they are associated with impairments in cognition common to several psychiatric disorders (Porteous et al., 2006). "
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    Frontiers in Genetics 07/2012; 3:116. DOI:10.3389/fgene.2012.00116
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    • "Recent studies have shown that RGS proteins are involved in CNS disorders. Abnormal RGS4 function has been implicated in schizophrenia (Mirnics et al. 2001; Morris et al. 2004; Williams et al. 2004; Prasad et al. 2005; Talkowski et al. 2006; Ding and Hegde 2009), anxiety (Leygraf et al. 2006), and Alzheimer's disease (Muma et al. 2003; Emilsson et al. 2006), and the striatal-enriched RGS9- 2 has been implicated in PD-related motor abnormalities (Gold et al. 2007) and in regulation of opiate analgesia in the dorsal horn (Papachatzaki et al. 2011) and striatum (Psifogeorgou et al. 2011). Polymorphisms in the RGS10 gene have also been reported in a cohort of Japanese schizophrenia patients (Hishimoto et al. 2004) and the modulation of both RGS4 and RGS10 by acute and chronic electroconvulsive seizures has been demonstrated in rat brain (Gold et al. 2002). "
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    Journal of Neurochemistry 05/2012; 122(2). DOI:10.1111/j.1471-4159.2012.07780.x · 4.24 Impact Factor
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    • "Interest in RGS4 was spearheaded by cDNA microarray and genomic analyses showing that transcription of RGS4 in prefrontal cortex (PFC) is decreased in a diagnosis-specific manner in patients with schizophrenia, and an association of schizophrenia with polymorphisms of the RGS4 gene (Mirnics et al. 2000, 2001; Chowdari et al. 2002). Several independent cohorts have since marshaled evidence to support RGS4 as a candidate schizophrenia susceptibility gene (Levitt et al. 2006; Talkowski et al. 2006), and have replicated marked loss of RGS4 protein from the PFC of patients with schizophrenia (Erdely et al. 2006). Recent studies in patients and healthy controls also indicate that allelic variations in RGS4 gene are associated with reduced PFC volume (Prasad et al. 2005; Buckholtz et al. 2007) and weaker prefrontal network activity during a working memory task (Buckholtz et al. 2007). "
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