谷氨酸能网络与精神分裂症的认知障碍有关：52种认知表型的全基因组关联研究
Glutamate Networks Implicate Cognitive Impairments in Schizophrenia: Genome-Wide Association Studies of 52 Cognitive Phenotypes.
作者信息
Ohi Kazutaka, Hashimoto Ryota, Ikeda Masashi, Yamamori Hidenaga, Yasuda Yuka, Fujimoto Michiko, Umeda-Yano Satomi, Fukunaga Masaki, Fujino Haruo, Watanabe Yoshiyuki, Iwase Masao, Kazui Hiroaki, Iwata Nakao, Weinberger Daniel R, Takeda Masatoshi
机构信息
Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD;
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;
出版信息
Schizophr Bull. 2015 Jul;41(4):909-18. doi: 10.1093/schbul/sbu171. Epub 2014 Dec 22.
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.
认知障碍是精神分裂症患者的核心特征。这些缺陷可作为理解精神分裂症遗传结构的有效工具。本研究调查了与认知障碍相关的基因变异是否聚集在与精神分裂症发病机制相关的功能基因网络中。在此，对411名健康受试者进行了一系列与精神分裂症相关的认知表型的全基因组关联研究（GWAS）。我们试图用257名精神分裂症患者复制GWAS数据，并对GWAS结果和复制结果进行荟萃分析。由于基因网络而非单个基因或基因变异可能与精神分裂症易感性和认知障碍密切相关，因此对与复制变异紧密相邻的基因进行了基因网络分析。我们在P < 1.0×10⁻⁴的阈值下观察到3054个变异与认知表型之间的名义关联。在这3054个变异中，191个变异的关联在复制样本中得到了验证（P < 0.05）。然而，在荟萃分析中没有变异达到全基因组显著性水平（P > 5.0×10⁻⁸）。此外，191个复制的单核苷酸多态性（SNP）中有115个（60.2%）其基因位于SNP的10 kb范围内。这些变异与认知表型呈中度关联，范围从P = 2.50×10⁻⁵到P = 9.40×10⁻⁸。与复制的SNP距离在10 kb以内的基因在谷氨酸受体活性（错误发现率（FDR）q = 4.49×10⁻¹⁷）和与主要组织相容性复合体I类相关的免疫系统（FDR q = 8.76×10⁻¹¹）网络方面显著聚集。我们的研究结果表明，与精神分裂症认知特质损害相关的基因变异参与了N-甲基-D-天冬氨酸谷氨酸网络。
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