Identification of single-nucleotide polymorphisms in the human N-methyl-D-aspartate receptor subunit NR2D gene, GRIN2D, and association study with schizophrenia
Identification of single-nucleotide polymorphisms in the human N-methyl-D-aspartate receptor subunit NR2D gene, GRIN2D, and association study with schizophrenia
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DOI：
10.1097/00041444-200509000-00014
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发表时间：
2005-09-01
影响因子：
0.9
通讯作者：
Fukumaki, Y
中科院分区：
文献类型：
--
作者：
Makino, C;Shibata, H;Fukumaki, Y
目的 谷氨酸能功能障碍是精神分裂症病理生理学的主要假说之一。 N-甲基-D-天冬氨酸受体引起人们的极大兴趣，因为苯环己哌啶（N-甲基-D-天冬氨酸受体的非竞争性拮抗剂）会产生类似精神分裂症的精神病。因此，编码N-甲基-D-天冬氨酸受体亚基的基因是精神分裂症易感基因的有力候选者。我们在精神分裂症病例对照研究中重点关注N-甲基-D-天冬氨酸受体亚基NR2D基因。方法通过直接测序对32名日本患者进行GRIN2D外显子、外显子-内含子边界和5'上游区域的多态性筛查。在鉴定的总共 13 个单核苷酸多态性中，我们对 200-201 名日本患者和 219-221 名对照者的 9 种常见单核苷酸多态性（次要等位基因频率超过 0.05）进行了基因分型。结果 9 种单核苷酸多态性中没有一个显示病例和对照之间的基因型和等位基因频率存在显着差异。我们在四种单核苷酸多态性（INT10SNP-EX13SNP2、EX13SNP2-EX13SNP3 和 EX6SNP-EX113SNP2）的三种组合中观察到成对单倍型与疾病的显着关联，即使在 Bonferroni 校正后（P = 1.094 X 10(-6)，P 校正 = 2.297x10(-5)，分别为P=2.825x10(-6)、P校正=5.933x10(-5)和P=2.02 x 10(-4)、P校正=4.242 x 10(-3)。在阈值 P 值 2.908 x 10(-3) 处使用错误发现率 (BL) 方法也获得了相同的结果。结论我们得出结论，GRIN2D 基因座可能是导致日本人群精神分裂症易感性的基因组区域。
Objectives The glutamatergic dysfunction is one of the main hypotheses for the pathophysiology of schizophrenia. N-methyl-D-aspartate receptors are of major interest because phencyclidine, a non-competitive antagonist of N-methyl-D-aspartate receptors, produces a schizophrenia-like psychosis. Therefore, the genes encoding N-methyl-D-aspartate receptor subunits are strong candidates for schizophrenia susceptibility genes. We focused on the N-methyl-D-aspartate receptor subunit NR2D gene in the case-control study of schizophrenia.Methods We screened for polymorphisms in exons, exon-intron boundaries and the 5' upstream region of GRIN2D by direct sequencing in 32 Japanese patients. Out of the total 13 single-nucleotide polymorphisms identified, we genotyped 200-201 Japanese patients and 219-221 controls for nine common single-nucleotide polymorphisms (minor allele frequency over 0.05).Results None of the nine single-nucleotide polymorphisms showed significant differences in genotype and allele frequencies between cases and controls. We observed significant associations of pairwise haplotypes in three combinations of four sing le-nucleotide polymorphisms, INT10SNP-EX13SNP2, EX13SNP2-EX13SNP3 and EX6SNP-EX113SNP2, with the disease even after the Bonferroni correction (P= 1.094 X 10(-6), P-corrected = 2.297x10(-5), P=2.825x10(-6), P-corrected=5.933x10(-5) and P= 2.02 x 10(-4), P-corrected=4.242 x 10(-3), respectively). The same results were also obtained using the false discovery rate (BL) method at the threshold P value, 2.908 x 10(-3).Conclusions We conclude that the GRIN2D locus is a possible genomic region contributing to schizophrenia susceptibility in the Japanese population.