Glutamate receptor ionotropic, NMDA 2D precursor (GluN2D) (EB11) (Glutamate [NMDA] receptor subunit epsilon-4) (N-methyl D-aspartate receptor subtype 2D) (NMDAR2D) (NR2D) [GluN2D] [NMDAR2D]
Disruption in normal development of the human prefrontal cortex (PFC) may lead to cognitive dysfunction that manifests in individuals with schizophrenia. We sought to identify genes associated with age that are implicated in schizophrenia. We generated genome-wide expression profiles for the PFCs of humans ranging in age from 1 month to 49 years using the Affymetrix HG-U133 plus 2.0 microarrays (54 675 transcripts). Based on the criteria of significance (false discovery rate [FDR]-adjusted q < 0.001 and r(2) > 0.6), we identified the genes associated with age in the PFC. We then performed functional annotation analyses of age-associated genes using the Gene Ontology and the Genetic Association Database (GAD). We found robust age-dependent changes in gene expression in the PFCs of humans (2281 transcripts). The GAD analysis revealed that schizophrenia was an over-represented disease class, with 42 susceptibility genes included (p < 0.001, fold enrichment = 1.66, FDR = 1.5%). Among the 42 genes, glutamate receptor genes (GRIA1, GRIK1, GRIK2, GRIN2D, GRIP1, GRM5, GRM7 and SLC1A6) were consistently downregulated across age. We confirmed microarray gene expression changes by the quantitative polymerase chain reaction experiment. Although numerous genes undergo robust changes in expression during the PFC development, some of the changes may be confounded by known and unknown factors that are intrinsic to the postmortem brain studies. Multiple schizophrenia susceptibility genes undergo age-dependent expression changes in the human PFC, and any disruption in those genes during the critical period of development may predispose the individuals to schizophrenia.
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