Supplementary table 1: from:- Carter C.J. Schizophrenia susceptibility genes directly implicated in the life cycles of pathogens: Cytomegalovirus, Influenza, Herpes simplex, Rubella, and T.Gondii. Schiz Bull,
Members of relevant gene families implicated in schizophrenia, in relation to the major processes disrupted in the disease: (glutamatergic signaling, dopamine, serotonin and GABA systems, oligodendrocyte function, growth-related processes, and oxidative stress). For references see Schizophrenia susceptibility genes
The genes implicated in viral and pathogen life cycles are also illustrated. For references see Schizophrenia microbes
As a rough comparison, the number of genes involved in each process is illustrated and also shown as a percentage of schizophrenia-related genes to date (currently N= 245)
Gene families and function |
Gene Families and symbols |
N and % of 245 |
Presynaptic vesicle packaging and glutamatergic metabolism, uptake, and release. |
|
12 = 4.9% |
Glutamate receptors:
Involved in learning and memory.
Antagonism of NMDA receptors (phencyclidine) |
|
13=5.3% |
Genes encoding for proteins forming part of the
NMDA receptor complex |
DLG2, DPYSL2, GRM3, GRM5, GRIN1, GRIN2A, GRIN2B, GRIN2D,HOMER1, LGI1, MOG, NOS1, NDUFV2, PLA2, PLP1, SLC1A2, STX1A,SYNGR1, YWHAH |
19=7.8% |
Genes encoding for proteins related to the
postsynaptic density |
Above and :-CALR, FYN, GABBR1, GAD1, GNAS, GRIA1, GRIA4, GRM3, GRM7, KIF2, NRXN1,NUMBl, PICK1, PDE4B, PIP5K2A, S100B, SLC25A1, SOD2, MAP6, SYN2, SYN3, XRCC1 + APC, DISC1 , DRPLA, NCAM1, NPTN, PAWR, PAX6, RGS4,ZDHHC8, GRIK3, GRIK4 |
52=24.2% |
GABA ergic system |
|
6=2.4% |
Dopamine receptors (Neuroleptics antagonise)
Dopamine transport and metabolism
Serotonin receptors (Neuroleptics antagonise)
Serotonin transport and metabolism |
DRD2, DRD3, DRD4, DRD5CHGB, SLC18A1, SLC18A2, SLC6A3, ADH1B, ALDH3B1, COMT, MAOA, PAH, TH, TYR YWHAHHTR2A, HTR3, HTR5A, HTR6, HTR7SLC6A4, MAOA, TPH1, YWHAH |
16 =6.5%
9=3.7% |
Growth factors and tyrosine kinase receptors
involved in cell growth and plasticity |
Growth factors: BDNF, EGF, NRG1, NRG2, NRG3, NTF3 Receptors: EGFR, ERBB2, ERBB4, FGFR1, GFRA1 |
11=4.4% |
Growth factor signaling:
Tyrosine kinases activate a phosphoinositide
kinase-signaling network culminating in the
activation of protein kinase B (AKT1).
These kinases and their diverse
phosphatidyl-phosphate
products are multifunctional and
play important roles in cellular signaling
and transport pathways. |
Phosphoinositide kinase PIK3C3, PIK3C2G Phosphatidylinositol 4-kinase PI4KA Phosphatidylinositol-4-phosphate 5-kinase PIP5K2A Inositol monophosphatase IMPA2 Protein kinase B (AKT1) |
6 =2.4% |
Axon guidance and neurite outgrowth |
ALK, AKT1, APOE, BDNF, CNR1, CNTF, EGF, EGFR, CHL1, CHN2, DISC1,DPYSL2, ERBB2. ERBB4, FEZ1, FGFR1, FYN, GRIN1, GRIN2A, GRIN2B,GRIN2D, HOMER, IL1B,IL2, KIF2A, KLH1AS, MAG, NRG1, NRG2, NRG3,NTNG1, NTNG2, PNOC, RTN4, RTN4R,SLIT3, PLXNA2 , S100B, TNF |
39=13% |
Adhesion molecules: Involved in cell-cell contact and with the connection of cells to the extracellular matrix. |
CHL1,NCAM1,CNTNAP2 ARCVF, a component of adherens junctions) |
4=1.6% |
Gap junctions: Connect the cytoplasm of two adjacent cells allowing the free passage of small molecules. |
Claudin (CLDN5), Connexin 50 (GJA8) |
2=0.8% |
Cytokines: Small protein messengers with key roles in immune defence, lymphocyte, and macrophage and microglial activation. Also play a neuromodulator role in CNS physiology. |
Interleukins IL1B, IL2, IL3, IL4, IL10, IL12B, IL18 Interleukin receptors IL3RA, IL10RA, IL18R1, IL18RAP Interleukin 1 receptor antagonist IL1RN Colony stimulating factor receptors CSF2RA, CSF2RB Lymphotoxin-alpha LTA Tumor necrosis factor TNF |
16=6.5% |
Immune system HLA molecules present antigens to T-cells |
HLA-A10, HLA-B, HLA-DRB1 MICB activates receptors on natural killer cells early growth response proteins :EGR2, EGR3, EGR4 CTLA4 (inhibits T-cell activation) |
8=3.2% |
Methionine and homocysteine metabolism |
MTHFR, MTR and MTHFD1 COMT and PEMT (Substrate + S-adenosyl-methionine Methylated product + S-adenosyl-L-homocysteine) |
5=2% |
Oxidative stress: Glutathione: Plays an important role in the detoxification of dopamine/catecholamine derived quinones: These are formed spontaneously and their formation can be limited by speeding the metabolism of dopamine through enyme-mediated metabolism (monoamine oxidase (MAOA, catechol-O-methyltransferase COMT). |
Glutathione synthases: GCLC, GCLM Glutathione transferases: GSTM1, GSTT1 Cysteine transporter SLC1A2 Quinone related: COMT: NQO2, S100B, TYR (+TH, MAOA) Oxidative stress: HP, ME2, ND4, NDUFV2, SOD2, UCP2, UCP4 |
18=7.3% |
Protein sorting folding and endoplasmic reticulum stress |
ATF6, CALR, HSPA1B, HSPA1L, XBP1 |
5=2% |
Oligodendrocyte-related |
ADCYAP1, BDNF, CNP1, CNR1, CNTF, DDR1, DRD2, DRD3, EGF,FGF1, GFRA1, IL1B, IL2, IL4, IL10, KLH1AS, LTA, NCAM1, OPRS1,NRG1, NRG2, NRG3, ERBB2, ERBB4, NOTCH4, NTF3, OLIG2, PAX6,PLP1, PSAP, SOX10, TNF, TF, QK1 |
34= 14% |
Circadian |
CLOCK, PER3, TIMELESS |
3=1% |
DISC1 : Disrupted in schizophrenia 1 and binding partners |
Important “Hub gene” at the centre of multiple processes;
Product binds to glutamate receptor scaffolds, the cytoskelatal and
microtubule network, proteins involved in growth development
and protein synthesis as well as to transcription factors involved in
oligodendrocyte development
and the control of stress pathways.
Binds to ATF4, DPYSL2, FEZ1, GABBR1, MLC1, NDE1, PDE4B |
8=3.2% |
Cytoskeletal components and transport |
Tubulin related (MAP6, TUBA2) BLOC-1 complex (Dysbindin (DTNBP1) Muted and BLOC1S3. Involved in endosome to lysosome transport Kinesin KIF2A PIK3C3, PI4KA, PIP5K2A |
9=3.7% |
Nuclear importins/karyopherins:
Transport cargoes from
the cytoplasm to the nucleus via nuclear pores. |
Beta importin RANBP5, Karyopherin alpha 5: KPNA5; |
2=0.8% |
Cyclic nucleotide Phosphodiesterases:
Metabolise cyclic AMP
and other nucleotides |
PDE4B: Phosphodiesterase 4B CNP1 (Oligodendrocyte marker) |
2=0.8% |
RNA polymerase: Mediator complex |
RNA polymerase creates an RNA copy from DNA or RNA. The mediator complex is a coactivator composed of several proteins including MED12 and MED15 |
2=0.8% |
Pathogen receptors
Involved in metabolism of chemical ligands
Ligand activated viral receptors |
AGA, B3GAT1 GALNT7, PLA2G4A, PLA2G4B, PLA2G4C, ST8SIA2EGFR, FGFR1, IL10RA |
11=4% |
Influenza related
Direct involvement in life cycle
(Binding, mimicry)
|
ACE, CALR, GRIN2B, HLA-B, HLA-DRB1, hsa-mir-198, KPNA3, PIK3C3, PIP5K2A, RANBP5, TPP2 |
11=4% |
Infuenza Other: effects on transcription etc |
AGA, AKT1, CCR5, CHN2, CTLA4, DLG2, EGR2, ENTH, ERBB4, FOXP2, GAD1, GALNT7, GCLC, GCLM, GSTM1,GSTT1,HOMER1,HSPA1B,IL10,IL18,IL1B, IL1RN,IL2,IL4,LTA,MDR1,MICB,NOS1,PI4KA, PLA2G4A, PLA2G4B, PLA2G4C, PLP1, PNPO, PTGS2, RELN, RGS4, SOD2, ST8SIA2,TNF, ZNF74 |
41=22% |
Total 52=21% |
||
Herpes simplex
Direct involvement in life cycle
(Binding, mimicry) |
APOE, ATF4, CALR, CHRNA7, FGFR1, FYN, HLA-B, KPNB3, PCQAP, TP53, TYR |
11=4.5% |
Herpes simplex all (effects on transcription, expression etc) |
ADCYAP1, AKT1, APC, CCR5, CHRNA7, CNP, CTLA4, EGR2, ERBB2,GALNT7, GCLC,GCLM, GNAS, GRIN1, GRIN2A, GRIN2B, GRIN2D,GSTM1, GSTT1, HOMER1, HTR2A,IL10, IL12, IL18, IL18RAP, IL1B,IL1RN, IL2, IL4, LTA, MED12, MICB, NOS1, NPY, NTF3,PICK1, PIK3C3, PLP1,PTGS2, SLC1A2, ST8SIA2,TH,TNF, ZNF74 |
44=17.9% |
Total =55=22.4% |
||
Cytomegalovirus
Direct involvement in life cycle (Binding, mimicry) |
CALR, EGFR, HSPA1B, HSPA1L, IL1B,IL10RA, MICB , PLA2 G4A, PLA2G4B, PLA2G4C |
11=4.5% |
Cytomegalovirus all
(effects on transcription, expression etc) |
AKT1, ATF4, B3GAT1, EGF, GCLC, GCLM, GRIN1, GSTM1, GSTT1, HLA-B , HLA-DRB1 ,IL10, IL12,IL12B,IL18,IL18R1,IL18RAP, IL1RN,IL2 ,IL4 ,KPNA3 LTA ,MAG MOG ,NCAM1,PTGS2 ,RANBP5 , ST8SIA2, TH,TNF,TP53,TPH,TYR, XBP1 ,ZNF74 |
35=14.2% |
Total=46=18.8% |
||
Rubella:
Direct involvement in life cycle
(Binding, mimicry) |
CALR, GAD1, HLA-DRB1, hsa-mir-198, MOG, PLP1 |
6=2.4% |
Rubella: Other
(effects on transcription, expression etc) |
AGA, AKT1, ENTH, HLA-B, IL10, PLA2G4A, PLA2G4B, PLA2G4C, TP53 |
9=3.7% |
Total =15=6.1% |
||
T.Gondii:
Direct involvement in life cycle
(Binding, mimicry) |
CCR5, HLA-B, NQO2, PAX6 |
4=1.6% |
T.Gondii Other
(effects on transcription, expression, etc) |
ACE, AKT1, CTLA4, DRD2, GCLC, GCLM, GNPAT, GSTM1, GSTT1, HLA-DRB1, HP, HSPA1B, IL10,IL12,IL1B,IL2,IL3,IL4,LTA,MDR1,NCAM1,ND4, NOS1, NRG2,PDE4B,PIK3C3,PNPO,PTGS2,SLC6A3,SOD2, ST8IA2, TF, TNF, TPH1, UCP2, YWHAHSOD2, |
36=14.7% |
Total=40=16.3% |
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