Identification of single-nucleotide polymorphisms in the human N-methyl-D-aspartate receptor subunit NR2D gene, GRIN2D, and association study with schizophrenia.
OBJECTIVE
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 single-nucleotide polymorphisms, INT10SNP-EX13SNP2, EX13SNP2-EX13SNP3 and EX6SNP-EX13SNP2, with the disease even after the Bonferroni correction (P=1.094 x 10(-6), Pcorrected=2.297 x 10(-5), P=2.825 x 10(-6), Pcorrected=5.933 x 10(-5) and P=2.02 x 10(-4), Pcorrected=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.
Makino
Chieko
C
Division of Disease Genes, Research Center for Genetic Information, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Shibata
Hiroki
H
Ninomiya
Hideaki
H
Tashiro
Nobutada
N
Fukumaki
Yasuyuki
Y
D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*
D016194:Receptors, N-Methyl-D-Aspartate