(1) In short, Gene Ontology analysis has identified several potentially affected pathways involved in synaptic transmission (HTR2A, BDNF, CHRNA3, CHRNB4, DRD1, DRD2, DRD4, EGR1, GRIA4, GRIN2B
, GRM3, NISCH, SLC1A3, and ERBB4), dopamine metabolic processes (COMT, DRD1, DRD2, DRD4, MAOA, NR4A2, and SLC6A3), and ion channel activity (CHRNA7, CACNA1I, CACNB2, CHRNA3, CHRNA5, CHRNB4, GABRB3, GRIA4, GRIA1, GRIN2B
, HCN1, CACNA1C, KCTD13, KCNV1, KCNN3, KCNJ13, and KCNB1).
For the current study, published in Psychiatric Genetics, the DNA sequences of over 4,000 people with schizophrenia and 5,000 controls were used to study variants in the three genes which code for NMDAR (GRIN1, GRIN2A and GRIN2B
) and a fourth (FYN), for a protein called Fyn which controls NMDAR functioning.
CalbindinD28k, NM_031984.1, UPL Probe #128 (Roche 04693647001); Parvalbumin, NM_022499.1, UPL Probe #49 (Roche 04688104001); Grin1 NM_001270602.1 UPL Probe #69 (Roche 04688686001); Grin2a NM_012573.3 UPL Probe #66 (Roche 04688651001); Grin2b
NM_012574.1 UPL Probe # 29 (Roche 04687612001); Grin2c NM_012575.3 UPL Probe #106 (Roche 04692250001); Grin2d NM_022797.1 UPL Probe #4 (Roche 04685016001); Grin3a NM_001198583.1 UPL Probe #105 (Roche 04692241001) CACNA1C, NM_012517.2, UPL Probe #73 (Roche 04688961001); CACNA1D, NM_017298.1, UPL Probe #82 (Roche 04689054001).
The GluN2B gene (GRIN2B
) is located on chromosome 12p12 and consists of 13 exons, the coding sequence being encompassed by exons 2 to 13.
Another gene identified in this group, GRIN2B
, encodes a subunit of a receptor that has roles in resilience of neurons and memory.
This view has been corroborated by a number of studies that found GRIN2B
to be implicated in phenotypes associated with rewards-related and impulsive behaviour such as smoking initiation (Vinik et al, 2009), alcoholism (Wernicke et al, 2003), pathological gambling (Lee et al, 2009), and obsessive-compulsive disorder (OCD [Arnold et al, 2009]).
De novo mutations in the GluN2B (GRIN2B
) and GluN2A (GRIN2A) genes have been identified in different cases of ASD and SCZ, respectively, as well as truncation mutations in GRIN1, GRIN2B
, and GRIN2A in ASD and SCZ patients .
Some well-known AD-related DEGs were dysregulated in our study, such as APP, CDK5R1, BACE2, PSENEN, GRIN2B
, ADAM10, and TNFRSF1A.
Table 3 Potential Pharmacogenetic Targets Detected in Human Postmortem Brain Studies in Alcohol-Dependent Subjects and Animal Studies Potential Altered Genes (Reference) Medication Targets Human Postmortem Studies Animal Studies Acamproate ([up arrow]) NMDA subunit ([down arrow]) GRIN1 with genes GRIN2B
and GRIN2D chronic ethanol use in in hippocampus (Enoch et dorsolateral prefrontal al.
Six loci (DAPK, HOXA1, CRABP1, TWIST1, GRIN2B
, and TIMP3) showed statistically higher methylation levels in adult samples than in pediatric samples (all values, P < .05, both Student t test and Mann-Whitney U test; Figure 4, A).
An association study of the N-methyl-D-aspartate receptor NRI subunit gene (GRIM) and NR2B subunit gene (GRIN2B
) in schizophrenia with universal DNA microarray.
Interestingly, CA1 minislices from pilocarpine-treated rats showed decreased expression of serine racemase and amino acid transporter Asc-1 but enhanced expression of D-amino oxidase and Grin2B
levels [20, 41] suggesting D-serine dysfunction in the CA1 area of pilocarpine-treated animals.