Determination of the genomic structure and mutation screening in schizophrenic individuals for five subunits of the N-methyl-D-aspartate glutamate receptor.
The glutamatergic system is the major excitatory neurotransmitter system in the CNS. Glutamate receptors, and in particular N-methyl-D-aspartate (NMDA) receptors, have been proposed as mediators of many common neuropsychiatric phenotypes including cognition, psychosis, and degeneration. We have reconstructed the genomic structure of all five genes encoding NMDA receptors in silico. We screened each for sequence variation and estimated the allele frequencies of all detected SNPs in pooled samples of 184 UK Caucasian schizophrenics and 184 UK Caucasian blood donor controls. Only a single non-synonymous polymorphism was found indicating extreme selection pressure. The rarity of non-synonymous changes suggests that such variants are unlikely to make a common contribution to common phenotypes. We found a further 26 polymorphisms within exonic or adjacent intronic sequences. The minor alleles of most of these have a relatively high frequency (63% above 0.2). These SNPs will therefore be suitable for studying neuropsychiatric phenotypes that are putatively related to NMDA dysfunction. Pooled analysis provided no support for association between any of the GRIN genes and schizophrenia.
Williams
N M
NM
Department of Psychological Medicine, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN, UK.
Bowen
T
T
Spurlock
G
G
Norton
N
N
Williams
H J
HJ
Hoogendoorn
B
B
Owen
M J
MJ
O'Donovan
M C
MC
D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics; D017124:Conserved Sequence; D017931:DNA Primers; D005091:Exons; D006801:Humans; D007438:Introns; D009419:Nerve Tissue Proteins / Q000235:genetics; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D021122:Protein Subunits / Q000235:genetics*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D012016:Reference Values; D012559:Schizophrenia / Q000235:genetics*; D006113:United Kingdom; D044465:White People / Q000235:genetics
D002352:Carrier Proteins; D017931:DNA Primers; C485668:GRIN1 protein, human; D009419:Nerve Tissue Proteins; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate