title: Comprehensive association analysis of 27 genes from the GABAergic system in Japanese individuals affected with schizophrenia.
abstract: Involvement of the gamma-aminobutyric acid (GABA)-ergic system in schizophrenia pathogenesis through disrupted neurodevelopment has been highlighted in numerous studies. However, the function of common genetic variants of this system in determining schizophrenia risk is unknown. We therefore tested the association of 375 tagged SNPs in genes derived from the GABAergic system, such as GABAAreceptor subunit genes, and GABA related genes (glutamate decarboxylase genes, GABAergic-marker gene, genes involved in GABA receptor trafficking and scaffolding) in Japanese schizophrenia case-control samples (n=2926; 1415 cases and 1511 controls). We observed nominal association of SNPs in nine GABAAreceptor subunit genes and the GPHN gene with schizophrenia, although none survived correction for study-wide multiple testing. Two SNPs located in the GABRA1 gene, rs4263535 (Pallele=0.002; uncorrected) and rs1157122 (Pallele=0.006; uncorrected) showed top hits, followed by rs723432 (Pallele=0.007; uncorrected) in the GPHN gene. All three were significantly associated with schizophrenia and survived gene-wide multiple testing. Haplotypes containing associated variants in GABRA1 but not GPHN were significantly associated with schizophrenia. To conclude, we provided substantiating genetic evidence for the involvement of the GABAergic system in schizophrenia susceptibility. These results warrant further investigations to replicate the association of GABRA1 and GPHN with schizophrenia and to discern the precise mechanisms of disease pathophysiology.
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Shabeesh
authors.initials: S
authors.lastname: Balan
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Iwayama
authors.affiliation: Department of Psychiatry and Neurobiology, Kanazawa University Graduate School of Medicine, Kanazawa 920-8641, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Hashimoto
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Toyota
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Shimamoto
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Motoko
authors.initials: M
authors.lastname: Maekawa
authors.affiliation: Department of Psychiatry, Hamamatsu University School of Medicine, Shizuoka 431-3192, Japan.
authors.forename: Shu
authors.initials: S
authors.lastname: Takagai
authors.affiliation: Department of Psychiatry, Hamamatsu University School of Medicine, Shizuoka 431-3192, Japan.
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Wakuda
authors.affiliation: Department of Psychiatry, Hamamatsu University School of Medicine, Shizuoka 431-3192, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kameno
authors.affiliation: Department of Psychiatry, Hamamatsu University School of Medicine, Shizuoka 431-3192, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kurita
authors.affiliation: Department of Psychiatry, Hamamatsu University School of Medicine, Shizuoka 431-3192, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Department of Psychiatry and Neurobiology, Kanazawa University Graduate School of Medicine, Kanazawa 920-8641, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Kikuchi
authors.affiliation: Department of Psychiatry, Graduate School of Medicine, Chiba University, Chiba 260-8677, Japan.
authors.forename: Tasuku
authors.initials: T
authors.lastname: Hashimoto
authors.affiliation: Department of Psychiatry, Graduate School of Medicine, Chiba University, Chiba 260-8677, Japan.
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Kanahara
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama 351-0198, Japan. Electronic address: takeo@brain.riken.jp.
authors.forename: Takeo
authors.initials: T
authors.lastname: Yoshikawa
mesh_terms: D000328:Adult; D000368:Aged; D044466:Asian People; D002352:Carrier Proteins / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005968:Glutamate Decarboxylase / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D018079:Receptors, GABA / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D005680:gamma-Aminobutyric Acid / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D018079:Receptors, GABA; C073441:gephyrin; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase
keywords: Association study; GABRA1; Gephyrin; SNP; Schizophrenia