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: 10.26). 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resolve the role for RGS4 in SCZ susceptibility, we undertook a genotype-based meta-analysis using both published and unpublished family-based and case-control samples (total n = 13,807).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, Sep 25, 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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    ABSTRACT: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are encoded by four genes (HCN1-4) and, through activation by cyclic AMP (cAMP), represent a point of convergence for several psychosis risk genes. On the basis of positive preliminary data, we sought to test whether genetic variation in HCN1-4 conferred risk of depression or cognitive impairment in the Generation Scotland: Scottish Family Health Study. HCN1, HCN2, HCN3, and HCN4 were genotyped for 43 haplotype-tagging SNPs and tested for association with DSM-IV depression, neuroticism, and a battery of cognitive tests assessing cognitive ability, memory, verbal fluency, and psychomotor performance. No association was found between any HCN channel gene SNP and risk of depression, neuroticism, or on any cognitive measure. The current study does not support a genetic role for HCN channels in conferring risk of depression or cognitive impairment in individuals from the Scottish population.
    Frontiers in Genetics 07/2012; 3:116. DOI:10.3389/fgene.2012.00116
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    • "Considering the close relationship between the RGS-Rz proteins and opioid receptors, and the association between opioid receptor genes and alcohol or drug dependence, we hypothesized that variation in RGS17 and RGS20 could affect vulnerability to various SD types. To date, no published studies have examined the association between RGS17 and RGS20 polymorphisms and SD or other psychiatric disorders, although associations between RGS2 variants and anxiety [23,24] and between RGS4 variants and schizophrenia [25,26] have been reported. We used a case–control association study approach to analyze the association of RGS17 and RGS20 variants and risk for four different SD diagnoses. "
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    ABSTRACT: RGS17 and RGS20 encode two members of the regulator of G-protein signaling RGS-Rz subfamily. Variation in these genes may alter their transcription and thereby influence the function of G protein-coupled receptors, including opioid receptors, and modify risk for substance dependence. The association of 13 RGS17 and eight RGS20 tag single nucleotide polymorphisms (SNPs) was examined with four substance dependence diagnoses (alcohol (AD), cocaine (CD), opioid (OD) or marijuana (MjD)] in 1,905 African Americans (AAs: 1,562 cases and 343 controls) and 1,332 European Americans (EAs: 981 cases and 351 controls). Analyses were performed using both χ2 tests and logistic regression analyses that covaried sex, age, and ancestry proportion. Correlation of genotypes and mRNA expression levels was assessed by linear regression analyses. Seven RGS17 SNPs showed a significant association with at least one of the four dependence traits after a permutation-based correction for multiple testing (0.003≤P(empirical)≤0.037). The G allele of SNP rs596359, in the RGS17 promoter region, was associated with AD, CD, OD, or MjD in both populations (0.005≤P(empirical)≤0.019). This allele was also associated with significantly lower mRNA expression levels of RGS17 in YRI subjects (P = 0.002) and non-significantly lower mRNA expression levels of RGS17 in CEU subjects (P = 0.185). No RGS20 SNPs were associated with any of the four dependence traits in either population. This study demonstrated that variation in RGS17 was associated with risk for substance dependence diagnoses in both AA and EA populations.
    Behavioral and Brain Functions 05/2012; 8(1):23. DOI:10.1186/1744-9081-8-23 · 1.97 Impact Factor
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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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    ABSTRACT: J. Neurochem. (2012) 122, 333–343. Regulator of G-protein signaling-10 (RGS10) is a GTPase activating protein for Gαi/q/z subunits that is highly expressed in the immune system and in a broad range of brain regions including the hippocampus, striatum, dorsal raphe, and ventral midbrain. Previously, we reported that RGS10-null mice display increased vulnerability to chronic systemic inflammation-induced degeneration of nigral dopaminergic (DA) neurons. Given that RGS10 is expressed in DA neurons, we investigated the extent to which RGS10 regulates cell survival under conditions of inflammatory stress. Because of the inherent limitations associated with use of primary DA neurons for biochemical analyses, we employed a well-characterized ventral mesencephalon DA neuroblastoma cell line (MN9D) for our studies. We found that stable over-expression of RGS10 rendered them resistant to TNF-induced cytotoxicity; whereas MN9D cells expressing mutant RGS10-S168A (which is resistant to phosphorylation by protein kinase A at a serine residue that promotes its nuclear translocation) showed similar sensitivity to TNF as the parental MN9D cells. Using biochemical and pharmacologic approaches, we identified protein kinase A and the downstream phospho-cAMP response element-binding signaling pathway (and ruled out ERK 1/2, JNK, and NFkB) as key mediators of the neuroprotective effect of RGS10 against inflammatory stress.
    Journal of Neurochemistry 05/2012; 122(2). DOI:10.1111/j.1471-4159.2012.07780.x · 4.28 Impact Factor
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