TY - JOUR
T1 - Glutamate Networks Implicate Cognitive Impairments in Schizophrenia
T2 - Genome-Wide Association Studies of 52 Cognitive Phenotypes
AU - Ohi, Kazutaka
AU - Hashimoto, Ryota
AU - Ikeda, Masashi
AU - Yamamori, Hidenaga
AU - Yasuda, Yuka
AU - Fujimoto, Michiko
AU - Umeda-Yano, Satomi
AU - Fukunaga, Masaki
AU - Fujino, Haruo
AU - Watanabe, Yoshiyuki
AU - Iwase, Masao
AU - Kazui, Hiroaki
AU - Iwata, Nakao
AU - Weinberger, Daniel R.
AU - Takeda, Masatoshi
N1 - Publisher Copyright:
© 2014 The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.
PY - 2015/7/1
Y1 - 2015/7/1
N2 - 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.
AB - 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.
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U2 - 10.1093/schbul/sbu171
DO - 10.1093/schbul/sbu171
M3 - Article
C2 - 25537281
AN - SCOPUS:84988267086
SN - 0586-7614
VL - 41
SP - 909
EP - 918
JO - Schizophrenia Bulletin
JF - Schizophrenia Bulletin
IS - 4
ER -
