Association of SNPs linked to increased expression of SLC1A1 with schizophrenia

Yasue Horiuchi, Syuhei Iida, Minori Koga, Hiroki Ishiguro, Yoshimi Iijima, Toshiya Inada, Yuichiro Watanabe, Toshiyuki Someya, Hiroshi Ujike, Nakao Iwata, Norio Ozaki, Hiroshi Kunugi, Mamoru Tochigi, Masanari Itokawa, Makoto Arai, Kazuhiro Niizato, Shuji Iritani, Akiyoshi Kakita, Hitoshi Takahashi, Hiroyuki Nawa & 1 others Tadao Arinami

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)30-37
Number of pages8
JournalAmerican Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Volume159 B
Issue number1
DOIs
Publication statusPublished - 01-01-2012

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Single Nucleotide Polymorphism
Schizophrenia
Glutamic Acid
Genes
Amino Acid Transport System X-AG
Prefrontal Cortex
Introns
Case-Control Studies
Real-Time Polymerase Chain Reaction
Signal Transduction
Alleles
Odds Ratio
Databases
Brain
Population

All Science Journal Classification (ASJC) codes

  • Genetics(clinical)
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Horiuchi, Yasue ; Iida, Syuhei ; Koga, Minori ; Ishiguro, Hiroki ; Iijima, Yoshimi ; Inada, Toshiya ; Watanabe, Yuichiro ; Someya, Toshiyuki ; Ujike, Hiroshi ; Iwata, Nakao ; Ozaki, Norio ; Kunugi, Hiroshi ; Tochigi, Mamoru ; Itokawa, Masanari ; Arai, Makoto ; Niizato, Kazuhiro ; Iritani, Shuji ; Kakita, Akiyoshi ; Takahashi, Hitoshi ; Nawa, Hiroyuki ; Arinami, Tadao. / Association of SNPs linked to increased expression of SLC1A1 with schizophrenia. In: American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics. 2012 ; Vol. 159 B, No. 1. pp. 30-37.
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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.",
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Horiuchi, Y, Iida, S, Koga, M, Ishiguro, H, Iijima, Y, Inada, T, Watanabe, Y, Someya, T, Ujike, H, Iwata, N, Ozaki, N, Kunugi, H, Tochigi, M, Itokawa, M, Arai, M, Niizato, K, Iritani, S, Kakita, A, Takahashi, H, Nawa, H & Arinami, T 2012, 'Association of SNPs linked to increased expression of SLC1A1 with schizophrenia', American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, vol. 159 B, no. 1, pp. 30-37. https://doi.org/10.1002/ajmg.b.31249

Association of SNPs linked to increased expression of SLC1A1 with schizophrenia. / Horiuchi, Yasue; Iida, Syuhei; Koga, Minori; Ishiguro, Hiroki; Iijima, Yoshimi; Inada, Toshiya; Watanabe, Yuichiro; Someya, Toshiyuki; Ujike, Hiroshi; Iwata, Nakao; Ozaki, Norio; Kunugi, Hiroshi; Tochigi, Mamoru; Itokawa, Masanari; Arai, Makoto; Niizato, Kazuhiro; Iritani, Shuji; Kakita, Akiyoshi; Takahashi, Hitoshi; Nawa, Hiroyuki; Arinami, Tadao.

In: American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, Vol. 159 B, No. 1, 01.01.2012, p. 30-37.

Research output: Contribution to journalArticle

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AU - Horiuchi, Yasue

AU - Iida, Syuhei

AU - Koga, Minori

AU - Ishiguro, Hiroki

AU - Iijima, Yoshimi

AU - Inada, Toshiya

AU - Watanabe, Yuichiro

AU - Someya, Toshiyuki

AU - Ujike, Hiroshi

AU - Iwata, Nakao

AU - Ozaki, Norio

AU - Kunugi, Hiroshi

AU - Tochigi, Mamoru

AU - Itokawa, Masanari

AU - Arai, Makoto

AU - Niizato, Kazuhiro

AU - Iritani, Shuji

AU - Kakita, Akiyoshi

AU - Takahashi, Hitoshi

AU - Nawa, Hiroyuki

AU - Arinami, Tadao

PY - 2012/1/1

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N2 - 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.

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