title: Glutamate Networks Implicate Cognitive Impairments in Schizophrenia: Genome-Wide Association Studies of 52 Cognitive Phenotypes.
abstract: Cognitive impairments are a core feature in patients with schizophrenia. These deficits could serve as effective tools for understanding the genetic architecture of schizophrenia. This study investigated whether genetic variants associated with cognitive impairments aggregate in functional gene networks related to the pathogenesis of schizophrenia. Here, genome-wide association studies (GWAS) of a range of cognitive phenotypes relevant to schizophrenia were performed in 411 healthy subjects. We attempted to replicate the GWAS data using 257 patients with schizophrenia and performed a meta-analysis of the GWAS findings and the replicated results. Because gene networks, rather than a single gene or genetic variant, may be strongly associated with the susceptibility to schizophrenia and cognitive impairments, gene-network analysis for genes in close proximity to the replicated variants was performed. We observed nominal associations between 3054 variants and cognitive phenotypes at a threshold of P < 1.0 × 10(-) (4). Of the 3054 variants, the associations of 191 variants were replicated in the replication samples (P < .05). However, no variants achieved genome-wide significance in a meta-analysis (P > 5.0 × 10(-) (8)). Additionally, 115 of 191 replicated single nucleotide polymorphisms (SNPs) have genes located within 10 kb of the SNPs (60.2%). These variants were moderately associated with cognitive phenotypes that ranged from P = 2.50 × 10(-) (5) to P = 9.40 × 10(-) (8). The genes located within 10 kb from the replicated SNPs were significantly grouped in terms of glutamate receptor activity (false discovery rate (FDR) q = 4.49 × 10(-) (17)) and the immune system related to major histocompatibility complex class I (FDR q = 8.76 × 10(-) (11)) networks. Our findings demonstrate that genetic variants related to cognitive trait impairment in schizophrenia are involved in the N-methyl-d-aspartate glutamate network.
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD;
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ohi
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Suita, Osaka, Japan; hashimor@psy.med.osaka-u.ac.jp.
authors.forename: Ryota
authors.initials: R
authors.lastname: Hashimoto
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan;
authors.forename: Masashi
authors.initials: M
authors.lastname: Ikeda
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Molecular Neuropsychiatry, Osaka University Graduate School of Medicine, Suita, Osaka, Japan;
authors.forename: Hidenaga
authors.initials: H
authors.lastname: Yamamori
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka, Japan;
authors.forename: Yuka
authors.initials: Y
authors.lastname: Yasuda
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka, Japan;
authors.forename: Michiko
authors.initials: M
authors.lastname: Fujimoto
authors.affiliation: Department of Molecular Neuropsychiatry, Osaka University Graduate School of Medicine, Suita, Osaka, Japan;
authors.forename: Satomi
authors.initials: S
authors.lastname: Umeda-Yano
authors.affiliation: Division of Cerebral Integration, National Institute of Physiological Sciences, Okazaki, Aichi, Japan;
authors.forename: Masaki
authors.initials: M
authors.lastname: Fukunaga
authors.affiliation: Graduate School of Human Sciences, Suita, Osaka, Japan;
authors.forename: Haruo
authors.initials: H
authors.lastname: Fujino
authors.affiliation: Department of Radiology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka, Japan;
authors.forename: Masao
authors.initials: M
authors.lastname: Iwase
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka, Japan;
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kazui
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan;
authors.forename: Nakao
authors.initials: N
authors.lastname: Iwata
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD;
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Suita, Osaka, Japan;
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takeda
mesh_terms: D000328:Adult; D003072:Cognition Disorders / Q000145:classification / Q000209:etiology / Q000235:genetics*; D005260:Female; D053263:Gene Regulatory Networks / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017470:Receptors, Glutamate / Q000378:metabolism*; D012559:Schizophrenia / Q000145:classification / Q000150:complications / Q000235:genetics*; D055815:Young Adult
chemical_list: D017470:Receptors, Glutamate
keywords: cognitive phenotypes; functional gene network; genome-wide association study; glutamate receptor activity; immune function; schizophrenia