Genes reported with genome-wide significance, or showing strong evidence for pathogenicity within deletions/duplications |
NMDAR/GRIN2A |
GWAS |
NMDA receptor subunit |
Lynchpin of synaptic plasticity at glutamatergic synapses |
GRM3 |
GWAS |
Metabotropic glutamate receptor 3 (mGluR3) |
May influence synaptic glutamate levels or NMDA receptor exocytosis |
AMPAR/GRIA1A |
GWAS |
Ionotropic glutamate receptor subunit |
Influences postsynaptic glutamate responsiveness. |
CACNA1C |
GWAS |
CaV1.2 voltage-gated calcium channel subunit |
Important in NMDA-independent synaptic plasticity in the hippocampus |
NRGN |
GWAS |
Neurogranin – calmodulin-binding protein |
Contributes to regulation of post-synaptic calcium levels and long-term potentiation |
MIR137 |
GWAS |
mir137 - microRNA |
Interferes with transcription of target mRNAs including CACNA1C, DPYD, CSMD1, ZNF804A and TCF4 |
TCF4 |
GWAS |
Transcription Factor 4 |
Targets may include other important schizophrenia related genes as well as stress/survival and developmental pathways. Haploinsufficiency causes Pitt-Rivers syndrome, a mental retardation syndrome. |
C10orf26 |
GWAS |
Unknown |
Unknown |
CACNB2, CACNA1I, CACNA1C |
GWAS |
Voltage-gated calcium channel subunit |
Unknown |
ZNF804A |
GWAS |
Zinc Finger Protein transcription factor |
Unknown |
TSNARE1 |
GWAS |
|
|
EPHX2 |
GWAS |
Epoxide hydrolyse 2 |
Inhibition reverses PCP (and NMDA antagonist)-induced changes to behavior in mice |
SRR |
GWAS |
Serine racemase |
Converts l-serine to d-serine, a co-agonist of NMDA receptors. Mouse SRR knockouts demonstrate NMDA hypofunction |
DRD2 |
GWAS |
Dopamine receptors |
DRD2 is the main site of antipsychotic action |
SLC38A7 |
GWAS |
Glutamine transporter |
May be involved in glutamate recycling in the synaptic cleft |
PLCH2 |
GWAS |
Intracellular calcium receptor |
Involved in calcium signalling during neural development |
NRXN1 |
Deletion, rare mutation |
Multiple splice variants yield neurexins – cell-cell adhesion molecules |
Involved in the formation, stabilisation and remodelling of both glutamatergic and glycinergic synapses together with NLGN. |
MEF2C |
GWAS |
Transcription factor |
Allosteric modulator of the NMDA receptor |
CNNM2 |
GWAS |
Cyclin M2 |
Important in renal regulation of magnesium |
VIPR2 |
Duplication |
G-protein-coupled VIPR receptor |
VIP known to regulate NMDA receptor activity in the hippocampus. |
|
Genes with weaker evidence of linkage to schizophrenia |
NRG1 |
Association |
|
NRG1-ErbB4 signalling pathway causes reduction of NMDA currents and long-term plasticity via phosphorylation of NR2B subunit. |
ErbB4 |
Association |
G72 |
Association |
d-amino acid oxidase activator |
G72 activates DAOA, which in turn degrades d-serine, a potent co-agonist at the glycine site of the NMDA receptor. |
DAAO |
Association |
d-amino acid oxidase |
DISC1 |
Association, linkage |
Disrupted in schizophrenia-1 |
Post-synaptic density protein involved in synaptic spine formation, NMDAR trafficking and presynaptic glutamate release. Also stabilises serine racemase. |
DTNBP1 |
Association, linkage |
Dysbindin |
Post-synaptic density protein which controls NMDAR expression, NMDA-mediated glutamate currents and glutamate release. |
COMT |
Linkage, deletion |
Catechol-O-methyltransferase |
Degrades dopamine and noradrenaline |
CHRNA7 |
Association, linkage |
Acetylcholine receptor |
|
GRM5 |
Rare mutation |
Metabotropic glutamate receptor 5 (mGluR5) |
Physically coupled to NMDAR at the post-synaptic density; co-activation potentiates NMDA currents |
PPEF2 |
Rare mutation |
Calmodulin-binding phosphatase |
Influences the levels of mGluR5 |
LRPB1 |
Rare mutation |
LDL-like receptor |
Competes for NMDA binding site on PSD-95 structural protein |
LRP1 |
Rare mutation |
LDL-like receptor |
Competes for NMDA binding site on PSD-95 structural protein |
PRODH |
Linkage, deletion, rare mutation |
Proline dehydrogynase |
NMDA receptor agonist at the glutamate binding site |