Gene networks related to cognitive function in schizophrenia identified

Gene networks related to cognitive function in schizophrenia identified

May lead to development of effective drugs for schizophrenia and cognitive impairment

Dec 24, 2014

A group of researchers led by HASHIMOTO Ryota (Associate Professor) and OHI Kazutaka (Researcher), United Graduate School of Child Development, Osaka University, conducted genetic analysis on cognitive functions such as learning, memory, and executive function, functions which are impaired in patients with schizophrenia. This group founded that glutamate through NMDA receptors and immune function network via major histocompatibility complex (MHC) are associated with cognitive functions in the disorder.

The pathogenetic mechanism of schizophrenia has not been clarified so discovery of genes and gene networks considered potential drug targets has been sought after. This group conducted a comprehensive genome-wide association study (GWAS) regarding 52 types of functions -- learning, memory, attention, executive function, and social cognition function -- in healthy subjects.

By making use of DNA chips, this group determined genetic polymorphism of more than 1 million Single Nucleotididene Polymorphism ( SNP ). By conducting genome-wide examination of relationships between SNPs and cognitive functions, this group identified the SNPs responsible for each cognitive function. In patients with schizophrenia, this group examined whether the detected SNPs were related to cognitive function and identified SNPs related to cognitive function in both healthy subjects and patients with schizophrenia. By examining gene networks in and in close proximity to identified SNPs, this group found that glutamate through NMDA receptors and immune function network via MHC are related to cognitive impairment in schizophrenia.This group's finding that gene networks related to cognitive impairment in schizophrenia means the discovery of drug target, the foundation for developing drugs for improving the situation, has likely been achieved. The development of drugs for these gene networks is expected to lead to the development of effective drugs for schizophrenia and cognitive impairment.


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.

To learn more about this research, please view the full research report entitled " Glutamate Networks Implicate Cognitive Impairments in Schizophrenia: Genome-Wide Association Studies of 52 Cognitive Phenotypes " at this page of the Schizophrenia Bulletin website.

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