Abstract
BackgroundBased on the glutamatergic dysfunction hypothesis for schizophrenia pathogenesis, we have been performing systematic association studies of schizophrenia with the genes involved in glutametergic transmission. We report here association studies of schizophrenia with SLC1A4, SLC1A5 encoding neutral amino acid transporters ASCT1, ASCT2, and SLC6A5, SLC6A9 encoding glycine transporters GLYT2, GLYT1, respectively.MethodsWe initially tested the association of 21 single nucleotide polymorphisms (SNPs) distributed in the four gene regions with schizophrenia using 100 Japanese cases-control pairs and examined allele, genotype and haplotype association with schizophrenia. The observed nominal significance were examined in the full-size samples (400 cases and 420 controls).ResultsWe observed nominally significant single-marker associations with schizophrenia in SNP2 (P = 0.021) and SNP3 (P = 0.029) of SLC1A4, SNP1 (P = 0.009) and SNP2 (P = 0.022) of SLC6A5. We also observed nominally significant haplotype associations with schizophrenia in the combinations of SNP2-SNP7 (P = 0.037) of SLC1A4 and SNP1-SNP4 (P = 0.043) of SLC6A5. We examined all of the nominal significance in the Full-size Sample Set, except one haplotype with insufficient LD. The significant association of SNP1 of SLC6A5 with schizophrenia was confirmed in the Full-size Sample Set (P = 0.018).ConclusionWe concluded that at least one susceptibility locus for schizophrenia may be located within or nearby SLC6A5, whereas SLC1A4, SLC1A5 and SLC6A9 are unlikely to be major susceptibility genes for schizophrenia in the Japanese population.
Highlights
Based on the glutamatergic dysfunction hypothesis for schizophrenia pathogenesis, we have been performing systematic association studies of schizophrenia with the genes involved in glutametergic transmission
Schizophrenia is a devastating mental disorder that affects about 1% of worldwide populations [1], and genetic factors are known to play a crucial role in its pathogenesis [2]
Based on the fact that phencyclidine (PCP), the antagonist of N-methyl-Daspartate (NMDA) glutamate receptor, induces schizophreniform psychosis, a glutamatergic dysfunction hypothesis has been proposed for the pathogenesis of schizophrenia [3,4,5]
Summary
Based on the glutamatergic dysfunction hypothesis for schizophrenia pathogenesis, we have been performing systematic association studies of schizophrenia with the genes involved in glutametergic transmission. Based on the fact that phencyclidine (PCP), the antagonist of N-methyl-Daspartate (NMDA) glutamate receptor, induces schizophreniform psychosis, a glutamatergic dysfunction hypothesis has been proposed for the pathogenesis of schizophrenia [3,4,5]. This hypothesis has been supported by recent multiple reports of significant association of schizophrenia with glutamate receptor genes and with the genes related to glutamatergic transmission [Review, [6,7]]. The dopamine and glutamate hypothesis of schizophrenia are not independent, and glutamatedopamine interaction has been supported by many preclinical and clinical findings [Review, [8]]
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