title: Association of SNPs linked to increased expression of SLC1A1 with schizophrenia.
abstract: Glutamate is one of the key molecules involved in signal transduction in the brain, and dysfunction of glutamate signaling could be linked to schizophrenia. The SLC1A1 gene located at 9p24 encodes the glutamate transporter EAAT3/EAAC1. To investigate the association between the SLC1A1 gene and schizophrenia in the Japanese population, we genotyped 19 tagging single nucleotide polymorphisms (tagSNPs) in the SLC1A1 gene in 576 unrelated individuals with schizophrenia and 576 control subjects followed by replication in an independent case-control study of 1,344 individuals with schizophrenia and 1,344 control subjects. In addition, we determined the boundaries of the copy number variation (CNV) region in the first intron (Database of Genomic Variants, chr9:4516796-4520549) and directly genotyped the CNV because of significant deviation from the Hardy-Weinberg equilibrium. The CNV was not associated with schizophrenia. Four SNPs showed a possible association with schizophrenia in the screening subjects and the associations were replicated in the same direction (nominal allelic P < 0.05), and, among them, an association with rs7022369 was replicated even after Bonferroni correction (allelic nominal P = 5 × 10(-5) , allelic corrected P = 2.5 × 10(-4) , allelic odds ratio, 1.30; 95% CI: 1.14-1.47 in the combined subjects). Expression analysis quantified by the real-time quantitative polymerase chain reaction in the postmortem prefrontal cortex of 43 Japanese individuals with schizophrenia and 11 Japanese control subjects revealed increased SLC1A1 expression levels in individuals homozygous for the rs7022369 risk allele (P = 0.003). Our findings suggest the involvement of SLC1A1 in the pathogenesis of schizophrenia.
authors.affiliation: Department of Medical Genetics, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Yasue
authors.initials: Y
authors.lastname: Horiuchi
authors.forename: Syuhei
authors.initials: S
authors.lastname: Iida
authors.forename: Minori
authors.initials: M
authors.lastname: Koga
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ishiguro
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Iijima
authors.forename: Toshiya
authors.initials: T
authors.lastname: Inada
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Someya
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ujike
authors.forename: Nakao
authors.initials: N
authors.lastname: Iwata
authors.forename: Norio
authors.initials: N
authors.lastname: Ozaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kunugi
authors.forename: Mamoru
authors.initials: M
authors.lastname: Tochigi
authors.forename: Masanari
authors.initials: M
authors.lastname: Itokawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Arai
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Niizato
authors.forename: Shuji
authors.initials: S
authors.lastname: Iritani
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Kakita
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nawa
authors.forename: Tadao
authors.initials: T
authors.lastname: Arinami
mesh_terms: D000483:Alleles; D001921:Brain / Q000473:pathology; D056915:DNA Copy Number Variations / Q000235:genetics; D050580:Excitatory Amino Acid Transporter 3 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011180:Postmortem Changes; D015203:Reproducibility of Results; D012559:Schizophrenia / Q000235:genetics*
chemical_list: D050580:Excitatory Amino Acid Transporter 3; C493400:SLC1A1 protein, human