A genomewide linkage study of age at onset in schizophrenia

University of South Wales, Понтиприте, Wales, United Kingdom
American Journal of Medical Genetics (Impact Factor: 3.23). 07/2001; 105(5):439-45. DOI: 10.1002/ajmg.1404
Source: PubMed


There is strong evidence for a genetic contribution to age at onset of schizophrenia, which probably involves both susceptibility loci for schizophrenia and modifying loci acting independent of disease risk. We sought evidence of linkage to loci that influence age at onset of schizophrenia in a sample of 94 affected sibling pairs with DSM-IV schizophrenia or schizoaffective disorder, and age at first psychiatric contact of 45 years or less. Individuals were genotyped for 229 microsatellite markers spaced at approximately 20 cM intervals throughout the genome. Loci contributing to age at onset were sought by a quantitative maximum-likelihood multipoint linkage analysis using MAPMAKER/SIBS. A nonparametric multipoint analysis was also performed. The genomewide significance of linkage results was assessed by simulation studies. There were six maximum-likelihood LOD score peaks of 1.5 or greater, the highest being on chromosome 17q (LOD = 2.54; genomewide P = 0.27). This fulfils Lander and Kruglyak's [1995: Nat Genet 11:241-247] criteria for suggestive linkage in that it would be expected to occur once or less (0.3 times) per genome scan. However, this finding should be treated with caution because the LOD score appeared to be almost solely accounted for by the pattern of ibd sharing at one marker (D17S787), with virtually no evidence of linkage over flanking markers. None of the linkage results achieved genomewide statistical significance, but the LOD score peak on chromosome 13q (LOD = 1.68) coincided with the region showing maximum evidence for linkage in the study by Blouin et al. [1998: Nat Genet 20:70-73] of categorical schizophrenia.

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    • "The age of onset has been considered the single most valuable characteristic of schizophrenia that may yield a clue to its origin [30]. A genomewide linkage study by Cardno et al. [35] has confirmed a genetic contribution to the age at onset of schizophrenia. This was the first time that significant associations of ESRα polymorphisms with age at onset of schizophrenia have been demonstrated. "
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    ABSTRACT: Background Estrogen is believed to play an important role in the central nervous system (CNS) and exert a protective role against schizophrenia. Estrogen receptor alpha (ESRα) mediates the biological action of estrogen. Rs2234693 and rs9340799, single nucleotide polymorphisms of ESRα, may be related to many psychiatric disorders, while their association with schizophrenia has not been clarified. Methods Genotypes rs2234693 and rs9340799 were detected in 303 schizophrenic patients and 292 healthy controls in a Chinese population. The positive and negative syndrome scale (PANSS) was used to estimate symptoms and therapeutic effects. The association of these polymorphisms with schizophrenia and clinical characteristics was analyzed by the chi-square test, analysis of variance, and others. Results The distribution of genotypes and allele frequencies of rs2234693 and rs9340799 exhibited no significant differences between patients and controls, while haplotypes consisting of these polymorphisms had significant differences. For 2234693, T-allele carriers had an earlier age at onset. CC-homozygote carriers had a higher general psychopathology score and its percentage reduction in male and paranoid patients, respectively. CC-homozygote carriers had a higher tension (G4) and poor impulse control (G14) score, mainly in paranoid patients. Furthermore, patients with the CC homozygote had higher reductions of G4 and G14 scores when treated by aripirazole and risperidone, respectively. Conclusions Haplotypes consisting of these two polymorphisms in ESRα may be strongly associated with schizophrenia. The rs2234693 was related to age at onset, general psychopathology, G4 and G14 symptoms, even the therapeutic effect in different groups.
    Behavioral and Brain Functions 03/2013; 9(1):12. DOI:10.1186/1744-9081-9-12 · 1.97 Impact Factor
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    • "An early age of onset has been associated with a range of more severe deficiencies in areas such as cognition, clinical and behavioral presentation, social ability, and brain ventricle sizes [Johnstone et al., 1989; Raz and Raz, 1990; Hoff et al., 1996; Eggers and Bunk, 1997; Rajji et al., 2009]. Age of onset in schizophrenia has been found to have genetic components [Cardno et al., 2001; Hare et al., 2010]. In a previous study, we reported association between the MTHFR C677T polymorphism and age at onset of schizophrenia in Scandinavian samples and a family sample from China [Vares et al., 2010]. "
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    ABSTRACT: Methylenetetrahydrofolate reductase (MTHFR) is involved in the one-carbon cycle, which is of importance for nucleotide synthesis and methylation of DNA, membranes, proteins and lipids. The MTHFR gene includes two common polymorphisms (rs1801133 or C677T; rs1801131 or A1298C) which both alter enzyme activity. The T-allele of the C677T polymorphism has recently been associated with earlier age at onset of schizophrenia. In the present study we examined the association between the MTHFR C677T and A1298C polymorphisms and age at onset of schizophrenia in twelve samples consisting of 3,213 unrelated schizophrenia patients, including the original Scandinavian sample. There was no consistent relationship between MTHFR C677T, A1298C or combined 677T/1298C carriers and age of onset in schizophrenia when the results of each study were combined using meta-analysis. The present results suggest that the investigated MTHFR polymorphisms do not influence age of onset in schizophrenia.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 03/2011; 156(2):215-24. DOI:10.1002/ajmg.b.31160 · 3.42 Impact Factor
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    • "The RGS9 gene is located on chromosome region 17q21-25 [11], and the region was implicated in major mental illness susceptibility through linkage studies [27-30]. We analyzed two SNPs, rs12452285 (Leu225Ser) and rs34797451 (His498Arg), of the RGS9 gene because these are the only two nonsynonymous polymorphisms in the RGS9 gene registered in the NCBI SNP database. "
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    ABSTRACT: The regulator of G-protein signaling (RGS) modulates the functioning of heterotrimeric G protein. RGS9-2 is highly expressed in the striatum and plays a role in modulating dopaminergic receptor-mediated signaling cascades. Previous studies suggested that the RGS9 gene might contribute to the susceptibility to psychotic diseases. Therefore, we investigated the association between the RGS9 gene and two related dopamine psychoses, schizophrenia and methamphetamine use disorders. The subjects comprised 487 patients of schizophrenia and 464 age- and sex-matched healthy controls and 220 patients of methamphetamine use disorder and 289 controls. We genotyped two nonsynonymous polymorphisms, rs12452285 (Leu225Ser) and rs34797451 (His498Arg), of the RGS9 gene. Rs34797451 showed monomorphism in the present Japanese population, but rs12452285 showed polymorphism. There were no significant differences in genotypic or allelic distributions of rs12452285 between patients with schizophrenia and the corresponding control or between patients with methamphetamine use disorder and the corresponding control. We also analyzed the clinical features of methamphetamine use disorder. We found a significant association in allelic distribution with the phenotypes of age at first consumption (p=0.047). The present study suggested that the RGS9 gene is unlikely to play a major role in schizophrenia and methamphetamine dependence liability and/or the development of methamphetamine induced psychosis, at least in a Japanese population.
    DNA research: an international journal for rapid publication of reports on genes and genomes 03/2011; 9(1):190-4. DOI:10.2174/157015911795017029 · 3.05 Impact Factor
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