Association of G72/G30 polymorphisms with early-onset and male schizophrenia

Abstract

To explore the e¡ect of G72/G30 polymorphisms on the clinical manifestations of schizophrenia, especially on the age at onset and sex of patients, we examined three single nucleotide polymorphisms in 216 schizophrenic patients and 321 healthy controls. Signi¢cant associations of schizophrenia with the A allele of rs947267 (P ¼ 0.012) and haplotype A-A-G (rs2391191-rs947267-rs778294) (P ¼ 0.008) were found in early-onset schizophrenic patients. So did the same allele (P ¼ 0.034) and haplotype (P ¼ 0.009) as mentioned above in male patients. These ¢ndings suggest that the G72/G30 gene may modulate the age at onset and there might be a potential interaction between this locus and sex in the pathogenesis of schizophrenia. NeuroReport17:1899^1902 c 2006 Lippincott Williams & Wilkins.Keywords: age at onset, association study, G72/G30, polymorphism, schizophrenia IntroductionSchizophrenia is a major psychiatric disorder that affects almost 1% of the world's population and accounts for about 2.5% of healthcare costs [1]. Symptoms usually begin in late adolescence or early adulthood. Involvement of neurodevelopmental mechanism, especially glutamatergic transmission via N-methyl-D-aspartate receptors and synaptic plasticity in schizophrenia, has been recently suggested, on the basis of several lines of evidence [2]. Linkage analyses on diverse samples have provided accumulating evidence that chromosome 13q32-q33 may be involved in susceptibility to schizophrenia. A meta-analysis of genomewide linkage studies further identified 13q32-q33 as significantly linked to schizophrenia [3].Chumakov et al.[4] first reported that genetic variations near G72 (MIN 607408) and G30 (MIN 607415) locus on 13q34 were associated with schizophrenia in FrenchCanadian and Russian cohorts. G72 and G30 overlap on complementary chromosomal strands and are therefore transcribed in opposite directions. By yeast two-hybrid experiments, Chumakov et al.[4] also identified that the G72 protein interacts with the enzyme D-amino acid oxidase (MIN 124050), which regulates glutamatergic signaling through an N-methyl-D-aspartate receptor pathway. Gene expression analysis of G72 and G30 exhibited correlations between expression levels of the G72 and G30 genes, as well as a tendency toward overexpression of G72 mRNA in schizophrenic post-mortem dorsolateral prefrontal cortex of 44 schizophrenic patients compared with 44 control participants [5].Hattori et al. [6] suggested that a susceptibility variant for both bipolar illness and schizophrenia exists in the vicinity of the G72/G30 gene in two series of pedigrees. Findings from several subsequent studies tend to advance a role for G72/G30 in the overall risk for schizophrenia and bipolar disorder from various populations, including a metaanalysis study and a research based on a sample of childonset schizophrenia [7][8][9][10][11][12][13][14]. The majority of replication studies have, however, been inconsistent with respect to the associated alleles or haplotypes. Moreover, negative associations of G72/G30 pol...

Allelic association of G72/G30 with schizophrenia and bipolar disorder: A comprehensive meta-analysis

“…Several studies were excluded because of sample duplication with another study (Yue et al, 2006), lack of sufficient data even after requesting informative data from the authors (Fallin et al, 2005;Goldberg et al, 2006;Hall et al, 2004;Nicodemus et al, 2007). M12, M15, M23 and M24 were excluded for BP because they were analyzed in only one or two studies (Schulze et al, 2005).…”

“…Shortly afterward, the G72/ G30 gene complex (G72 is now officially known as D-aminoacid oxidase activator, DAOA) was associated, independently, with each disorder (Chumakov et al, 2002;Hattori et al, 2003). An association has been reported in multiple independent studies (Addington et al, 2004;Chen et al, 2004;Fallin et al, 2005;Hall et al, 2004;Hong et al, 2006;Korostishevsky et al, 2004;Korostishevsky et al, 2006;Ma et al, 2006;Schulze et al, 2005;Schumacher et al, 2004;Wang et al, 2004;Williams et al, 2006;Yue et al, 2006;Yue et al, 2007;Zou et al, 2005). However, several studies did not find association with traditional BP or SCZ phenotype (Bakker et al, 2007;Goldberg et al, 2006;Liu et al, 2006;Mulle et al, 2005;Vilella et al, 2007;Wood et al, 2006).…”

“…Since then, 13 more G72/G30 association studies in SCZ and three more in BP have been published (Bakker et al, 2007;Fallin et al, 2005;Goldberg et al, 2006;Hong et al, 2006;Korostishevsky et al, 2006;Liu et al, 2006;Ma et al, 2006;Nicodemus et al, 2007;Schulze et al, 2005;Vilella et al, 2007;Williams et al, 2006;Wood et al, 2006;Yue et al, 2006;Yue et al, 2007), with inconsistent associated alleles or haplotypes. Here we report an updated meta-analysis to re-evaluate the relationship between variants in the G72/G30 gene region and these two major psychiatric disorders.…”

Two-stage designs to identify the effects of SNP combinations on complex diseases

“…Seventeen SNPs were genotyped across these four candidate genes in the Chinese Han population, which included 120 schizophrenia cases and 225 healthy controls. Prior reports have suggested that variations in the genes may be associated with increased risk of paranoid schizophrenia (Yue et al 2006(Yue et al , 2007Zhang et al 2004;Harrison and Owen 2003). Model 1: P(Disease|AAbb) = 0.02, P(Disease|AaBb) = 0.2, P(Disease|aaBB) = 0.02, and P(Disease|others) = 0; Model 2: P(Disease|AAbb) = 0.2, P(Disease|AaBb) = 0.2, P(Disease|aaBB) = 0.2, and P(Disease|others) = 0, where A, a, B and b represent the alleles for the disease loci and P(A) = P(B) = 0.3 in these two models * Here we choose u a/2 = 3 as a threshold for the selection of associated SNP patterns…”

“…This method is applied to a case-control schizophrenia study from a Chinese Han population to detect the effects of 17 loci of four candidate genes, the regulator of Gprotein signaling-4 (RGS4, 1q21-q22), frizzled 3 (FZD3, 8p21), neuregulin 1 (NRG1, 8p22-p11), and G72 (13q34), on the susceptibility to this disease, since these have been reported in other studies to be possible candidate genes for schizophrenia (Yue et al 2006(Yue et al , 2007Zhang et al 2004;Harrison and Owen 2003).…”