Dataset Information

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.

SUBMITTER: Ohi K

PROVIDER: S-EPMC4466179 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Glutamate Networks Implicate Cognitive Impairments in Schizophrenia: Genome-Wide Association Studies of 52 Cognitive Phenotypes.

Ohi Kazutaka K Hashimoto Ryota R Ikeda Masashi M Yamamori Hidenaga H Yasuda Yuka Y Fujimoto Michiko M Umeda-Yano Satomi S Fukunaga Masaki M Fujino Haruo H Watanabe Yoshiyuki Y Iwase Masao M Kazui Hiroaki H Iwata Nakao N Weinberger Daniel R DR Takeda Masatoshi M

Schizophrenia bulletin 20141222 4

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 ...[more]

PMID: 25537281

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Project description:Cognitive deficits contribute to functional disability in patients with schizophrenia and may be related to altered functional networks that serve cognition. We evaluated the integrity of major functional networks and assessed their role in supporting two cognitive functions affected in schizophrenia: processing speed (PS) and working memory (WM). Resting-state functional magnetic resonance imaging (rsfMRI) data, N = 261 patients and 327 controls, were aggregated from three independent cohorts and evaluated using Enhancing NeuroImaging Genetics through Meta Analysis rsfMRI analysis pipeline. Meta- and mega-analyses were used to evaluate patient-control differences in functional connectivity (FC) measures. Canonical correlation analysis was used to study the association between cognitive deficits and FC measures. Patients showed consistent patterns of cognitive and resting-state FC (rsFC) deficits across three cohorts. Patient-control differences in rsFC calculated using seed-based and dual-regression approaches were consistent (Cohen's d: 0.31?±?0.09 and 0.29?±?0.08, p?<?10-4 ). RsFC measures explained 12-17% of the individual variations in PS and WM in the full sample and in patients and controls separately, with the strongest correlations found in salience, auditory, somatosensory, and default-mode networks. The pattern of association between rsFC (within-network) and PS (r = .45, p = .07) and WM (r = .36, p = .16), and rsFC (between-network) and PS (r = .52, p = 8.4?×?10-3 ) and WM (r = .47, p = .02), derived from multiple networks was related to effect size of patient-control differences in the functional networks. No association was detected between rsFC and current medication dose or psychosis ratings. Patients demonstrated significant reduction in several FC networks that may partially underlie some of the core neurocognitive deficits in schizophrenia. The strength of connectivity-cognition relationships in different networks was strongly associated with network's vulnerability to schizophrenia.

Dataset Information

Glutamate Networks Implicate Cognitive Impairments in Schizophrenia: Genome-Wide Association Studies of 52 Cognitive Phenotypes.

Publications

Glutamate Networks Implicate Cognitive Impairments in Schizophrenia: Genome-Wide Association Studies of 52 Cognitive Phenotypes.

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