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The tables below contain lists of genes reported to be associated with Bipolar disorder. Negative studies also exist for many of these genes, but are not reported. Each gene is linked to its ENTREZ gene ID. The PUBMED links are designed to collect general data in relation to Bipolar disorder, rather than specific association data. Protein/protein or transriptional control interactions are generally culled from ENTREZ gene data unless specified. Pubmed, Entrez and OMIM data are provided by the NCBI .KEGG pathway data is provided by the Kanehisa Laboratories (www.kegg.org). For KEGG licensing conditions, please contact Pathway Solutions Inc. (www.pathway.jp) . Kegg pathway maps containing these genes are available here. GeneCards links are with the kind permission of GeneCards.org. ENVIRONMENTAL RISK FACTORS ARE INCLUDED AT THE BOTTOM OF THESE TABLES
Table 1: Genes associated with both Bipolar disorder and Schizophrenia (See Carter 2006 and this page for schizophrenia genes)
| PI3K/AKT signalling, growth factors and related | AKT1, BDNF, EGFR, IMPA2, NCAM1, NRG1, PIK3C3, PIP5K2A, PDLIM5, RGS4 |
| NMDA and glutamate-related | DAO, DAOA, DTNBP1, GRID1, GRIN1, GRIN2A, GRIN2B, GRIK4, GRM3, GRM4, NOS1, NOSIAP, SYN3 |
| Dopaminergic/Serotonergic | COMT, DRD2, DRD3, HTR2A, HTR5A, HTR6, SLC6A3, SLC6A4,SLC18A1, SLC18A2, MAOA, TH |
| Circadian | CLOCK, TIMELESS, PER3 |
| Cytokines | CSF2RB, IL1B, IL1RN, TNFA |
| Oxidative and other stress | ND4, NDUFV2, MTHFR, MTHFD, MTR |
| Endoplasmic reticulum stress | XBP1 |
| Miscellaneous | APOE, BRD1, CHRNA7, DISC1, DPYSL2, GPR50, MLC1, PPP3CC, SLIT3, SYNGR1, YWHAH |
Table 2:Growth factors: Phosphatidyl-inositol metabolism and PI3K/AKT1 signaling and tyrosine kinase pathway related genes
|
Genes
associated with bipolar disorder |
Association
studies |
Primary
role |
Links
to other Bipolar genes |
Expression
changes |
BDNF brain
derived neurotrophic factor OMIM OMIM
|
A number
of studies suggest association of this gene with bipolar disorder (Geller
et al. 2004;Lohoff et al. 2005;Rybakowski et al. 2003;Neves-Pereira
et al. 2002). Its
protein levels are decreased in the hippocampus of Bipolar disorder
patients (Knable
et al. 2004). PUBMED |
Growth
factor activating the PI3K/AKT cascade (Gavalda
et al. 2004) |
Expression
stimulated by NMDA receptor activation (GRIN1,
GRIN2A) and by DRD1(Fang
et al. 2003),(Kuppers
and Beyer 2001) and DRD2 (Takeuchi
et al. 2002) receptor
stimulation. Controls TH (Zhou
et al. 1998) and SLC6A4 (Mossner
et al. 2000), (Rumajogee
et al. 2002). expression(Zhou
et al. 1994;Zhou et al. 1997). |
Decreased
hippocampal protein levels in schizophrenia and Bipolar disorder (Knable
et al. 2004). Serum
levels decreased during depressive and manic episodes (Cunha
et al. 2006). |
|
NRG1 Neuregulin
1 OMIM GeneCard |
This
gene, associated with schizophrenia in many studies (Stefansson
et al. 2002;Stefansson et al. 2003;Williams et al. 2003;Yang et al.
2003)has
also been classified as a susceptibility gene in bipolar disorder (Green
et al. 2005). PUBMED |
Glial
growth factor |
Activates
the PI3K/AKT pathway (Flores
et al. 2000). Reduces
NMDA currents and increases internalization of GRIN1 (Gu
et al. 2005).(Li
et al. 2003). Released
from cultured Schwann cells by BDNF (Esper
and Loeb 2004). |
Decreased
mRNA expression in prefrontal cortex (Tkachev
et al. 2003). Stanley
consortium Combined analysis: Unchanged (Higgs
et al. 2006) |
| EGFR epidermal growth factor receptor (erythroblastic leukemia viral (v-erb-b) oncogene homolog, GeneCard | WGA Sklar et al, 2008 | EGF receptor | Activates PI3K/AKT pathway | |
|
v-akt
murine thymoma viral oncogene homolog 1 14q32.32 |
Weak evidence for association in a Bipolar pedigree (Toyota et al. 2003). PUBMED |
Survival
factor activated via growth factor stimulation of PI3 kinases. Phosphorylates
and inhibits elements of the apoptotic pathway. |
Phosphatidylinositol
3 phosphate (Product of PIK3C3 activates AKT1 (Franke
et al. 1995) BDNF, CCL2 activate AKT1 (Selzman
et al. 2002;Turner et al. 1997;Lentzsch et al. 2003). Angiotensin
II (cf AGT) stimulates AKT1 (Griendling
and Ushio-Fukai 2000;Chiu et al. 2004). Phosphorylation
targets include GSK3B (inactivated) (Shaw
et al. 1997), NMDA
receptors (GRIN1) activated, NOS3 (activated)(Wu
2002) |
Stanley
consortium Combined analysis: Unchanged (Higgs
et al. 2006) |
|
BCR breakpoint
cluster region 22q11.23 High
incidence of Bipolar disorder in 22q11 deletion syndrome (Papolos
et al. 1996) |
BCR has been associated with major depression and bipolar disorder (Hashimoto et al. 2005). |
Serine-threonioneKinase
and GTPase activating protein |
Binds
to PLCG1 and the P85 unit of phosphatidylinositol 3 kinase (Muller
et al. 1992). Tyrosine
phosphorylated BCR binds to the adapter molecule growth factor
receptor-bound protein 2 (GRB2) (Ma
et al. 1997) which
links the EGF receptor tyrosine kinase to Ras activation and that
of its downstream kinases ERK1 and ERK2. GRB2 is involved in several
growth factor signaling pathways including those mediated by NGF
and BDNF (Araki
et al. 2000;Yamada et al. 1999;Qian et al. 1998) |
Stanley
consortium Combined analysis: Unchanged (Higgs
et al. 2006) |
| SYK Spleen tyrosine kinase GeneCard | Wellcome Trust Case control Consortium | Important role in leukocyte signaling pathways and in phagocytic cell activation. | BCR signaling Takata et al, 1994) .Coupled to IL2RB Miyazaki and Tanaguchi, 1996 | |
| DGKH diacylglycerol kinase, eta GeneCard | Genome-wide association study Baum et al, 2007
|
Output of the PI signalling cascade Kegg (2.7.1.107) | ||
|
Dual
specificity phosphatase 6 12q22-q23 12q23-24
region linked to Bipolar disorder in UK
studies (Glaser
et al. 2005b) |
Association reported in a Korean study (Lee et al. 2006a) |
Binds
to and inactivates erk1 (MAPK3)
and erk2 (MAPK1)
(downstream components of growth factor receptor signaling) (Muda
et al. 1998). |
|
Stanley
consortium Combined analysis: Downregulated (Higgs
et al. 2006) |
|
FAT FAT
tumor suppressor homolog 1 4q35 |
Association reported in an Australian case and family study (Blair et al. 2006) |
Cell-cell
adhesion cadherin involved in cell migration Binds to ENAH, VASP and
MENA |
Binds
to beta catenin (Cox et al. 2000) |
Stanley
consortium Combined analysis: Unchanged (Higgs
et al. 2006) |
| GAB2 GRB2-associated binding protein 2 GeneCard | Genome-wide association study Baum et al, 2007 | Adaptor protein transmitting growth factor signals to PI3K/ AKT pathway | Phosphorylated by AKT1 Lynch and Daly, 2002 Binds to PLCG2 Mao et al, 2006 | |
|
Glycogen
synthase kinase 3 beta 3q13.3
? |
A polymorphism in the promoter region of GSK3B influences the age of onset of bipolar disorder. However, its frequency is not different from that in he normal population (Benedetti et al. 2004b;Benedetti et al. 2004a). Assdociation resticted to female patients in a Polish study(Szczepankiewicz et al. 2006) |
Phosphorylates
and inactivates glycogen synthase.Involved in energy metabolism and
neuronal development. Inhibited
by lithium and valproate (Chen
et al. 1999;Klein and Melton 1996) |
Phosphorylated
by AKT1 (Takahashi-Yanaga
et al. 2004).HTR2A receptors
decrease GSK3B phosphorylation (Li
et al. 2004). Wnt
activation by GSK3B inhibition is suppressed by myoinositol (Hedgepeth
et al. 1997) the
putative product of IMPA2. BDNF increases -phosphorylation
of GSK3B PDGF phosphorylates GSK3B via
activation of PLCG1 (Fang
et al. 2002). Phosphorylates KCNQ2(Borsotto
et al. 2006) |
No mRNA
expression change in frontal or occipital cortex (Agam
et al. 2003). RNA
downregulated in dorsolateral prefrontal cortex (Nakatani
et al. 2006). Protein
unmodified in prefrontal cortex (Beasley
et al. 2002) Stanley
consortium Combined analysis: Unchanged (Higgs
et al. 2006;Lesort et al. 1999) |
|
IMPA2 inositol(myo)-1(or 4)-monophosphatase 2 OMIM GeneCard 18p11.2 Described as a Bipolar disorder locus in several studies (Detera-Wadleigh et al. 1999;Esterling et al. 1997;McInnes et al. 2001;Mors et al. 1997) |
A polymorphism in this gene associates with bipolar disorder in Palestinian and Norwegian populations (Sjoholt et al. 2004b) . (Sjoholt et al. 2004a). |
Inositol
monophosphatases regenerate inositol from inositol monophosphates
(the breakdown productes of inositol triphosphate) and are a target
of lithium, which inhibits magnesium binding to the enzymes (Hallcher
and Sherman 1980).
High concentrations of lithium repress IMPA2 promoter activity
and expression in HeLa cells (Seelan
et al. 2004). |
|
IMPA2 expression
is decreased in B lymphoblast cell lines from bipolar patients and
increased in the temporal cortex in male bipolar subjects (Yoon
et al. 2001) Stanley
consortium Combined analysis: Unchanged (Higgs
et al. 2006) |
|
KCNQ2 potassium
voltage-gated channel, KQT-like subfamily, member 2 20q13.3 |
Association reported in a French study (Borsotto et al. 2006) |
- |
Activated
by phosphatidylinositol 4,5 biphosphate, product of PIP5K2A (Zhang
et al. 2003). Phosphorylated
by GSK3B, dephosphorylated by PPP2R2C (Borsotto
et al. 2006) |
Stanley
consortium Combined analysis: Unchanged (Higgs
et al. 2006) |
|
PPP2R2C protein
phosphatase 2 (formerly 2A), regulatory subunit B (PR 52), gamma
isoform 4p16.1 |
Association reported in a French study (Borsotto et al. 2006) |
|
Dephosphorylates
and activates KCNQ2 (Borsotto
et al. 2006) |
Stanley
consortium Combined analysis: Unchanged (Higgs
et al. 2006) |
|
PIK3C3 phosphoinositide-3-kinase, class 3 OMIM 602609 GeneCard (VPS34) 18q12.3 Described
as a susceptibility locus in a Canadian study (Maziade
et al. 2005) |
A promoter variant of this gene is associated with with bipolar disorder and schizophrenia (Stopkova et al. 2004a). |
Phosphoinositide
kinase. Converts Phosphatidylinositol
to Phosphatidylinositol 3 phosphate (Volinia
et al. 1995). Nutrient
regulated and inhibited by glucose or amino acid deprivation. Involved
in the trafficking of EGF and PDGF receptors (Futter
et al. 2001;Siddhanta et al. 1998) |
Product
metabolised by PIP5K2A |
Stanley
consortium Combined analysis: Unchanged (Higgs
et al. 2006) |
|
PIK4CA phosphatidylinositol
4-kinase, catalytic, alpha polypeptide 22q11.21. High
incidence of Bipolar disorder in 22q11 deletion syndrome (Papolos
et al. 1996) |
Suggestive association in an American study (Saito et al. 2003) |
Converts Phosphatidylinositol
to Phosphatidylinositol 4 phosphate: Role in EGF receptor trafficking
and degradation (Minogue
et al. 2006). |
- |
Stanley
consortium Combined analysis: Unchanged (Higgs
et al. 2006) |
|
PLCG1 20q12-q13.1 Region
linked to psychotic bipolar disorder (Park
et al. 2004) |
Moderate evidence for association in Canadian and Norwegian patients (Lovlie et al. 2001) |
Catalyzes
the formation of inositol 1,4,5-trisphosphate and diacylglycerol
from phosphatidylinositol 4,5-bisphosphate, one of the products of PIP5K2A. |
Bind
to BCR (Muller
et al. 1992) GNAZ (Bartlett
and Hendry 1997) GRIN2A (Gurd
and Bissoon 1997a), GRIN2B (Gurd
and Bissoon 1997b) inhibited
by SYNJ1 (Ahn
et al. 1998) DRD1 activates PLCG1 via
PKA (Yu et
al. 1996) .
The NRG1 receptor ERBB2 binds to and tyrosine phosphorylates PLCG1 (Peles
et al. 1991). Binds
to GRB2 (Pei
et al. 1997) |
Stanley
consortium Combined analysis: Unchanged (Higgs
et al. 2006) |
| PLCG2 phospholipase C, gamma 2 (phosphatidylinositol-specific) GeneCard | Genome-wide association study Baum et al, 2007 | see above | Binds to GAB2 Mao et al, 2006 | |
|
PIP5K2A phosphatidylinositol-4-phosphate 5-kinase, type II, alpha OMIM GeneCard 10p12.2 Region
linked to Bipolar disorder in a Genome-wide linkage scan (NIMH) (Cheng
et al. 2006) |
Modest association of polymorphisms with bipolar disorder and schizophrenia (Stopkova et al. 2003) |
Metabolises
the PIK3C3 product Phosphatidylinositol 3 phosphate to phosphatidylinositol
3,4-biphosphate and phosphatidylinositol 3,4,5-triphosphate (Zhang
et al. 1997). Also
metabolises the PIK4CA product phosphatidylinositol-4-phosphate,
and phosphatidylinositol-5-phosphate (Rameh
et al. 1997) (products
of phosphatidylinositol 4- and 5-kinases to phosphatidylinositol-4,5-bisphosphate (Loijens
et al. 1996) and
is thus capable of generating multiple second messengers. |
Substrate
generated by PIK3C3, and PIK4CA Products metabolised
by SYNJ1. PIP5K2A product
PI 4,5 P2, inhibits ADRBK2 (Onorato
et al. 1995) and RGS4 (Ishii
et al. 2005). |
Stanley
consortium Combined analysis: Unchanged (Higgs
et al. 2006) |
|
RGS4 regulator of G-protein signalling 4 See Review
of genome scan studies (Levinson
2005) |
Suggestive association in a Brazilian study (Cordeiro et al. 2005) |
GTPase-activating
protein |
GTPase
activating property is inhibited by phosphatidylinositol 3,4,5-trisphosphate,
the product of PIP5K2A (Ishii
et al. 2005). |
Stanley
consortium Combined analysis: Downregulated (Higgs
et al. 2006) |
| SHOC2 soc-2 suppressor of clear homolog (C. elegans) GeneCard | Genome-wide association study Baum et al, 2007 | Involved in the transduction of growth factor to MAPK signaling Rodriguez-Viciana et al, 2006 |
||
|
21q22.2 Region linked to bipolar
disorder (Detera-Wadleigh
et al. 1999;McQuillin et al. 2005) |
Rare mutations of this gene have been observed in a small number of bipolar patients (Stopkova et al. 2004b;Saito et al. 2001). |
Multifunctional
enzyme that can remove the 5 terminal phosphates of several phosphoinositides
and inositol polyphosphates including Phosphatidylinositol (4,5)
biphosphate, Phosphatidylinositol (3,4,5) triphosphate and Inositol
triphosphate. It can also convert Phosphatidylinositol (3) P, Phosphatidylinositol
(4)P and Phosphatidylinositol(3,5)P2 into Phosphatidylinositol (Johenning
et al. 2004). It
can thus be considered as the reverse equivalent of PIK3C3,
PIK4CA and PIK5K2A. |
Associates
with and Inhibits PLCG1 (Ahn
et al. 1998). Binds
to GRB2 (McPherson
et al. 1994). |
Stanley
consortium Combined analysis: Unchanged (Higgs
et al. 2006) |
|
TCF4 (E2-2,
ITF2, SEF2, SEF2-1, SEF2-1A, SEF2-1B) 18q12-q21described
as a susceptibility locus in a Canadian study (Maziade
et al. 2005) |
A number of groups have reported association of CAG repeats within the CTG18.1 locus with Bipolar disorder (Del Favero et al. 2002;Jin et al. 2001;Parikh et al. 1999;Lindblad et al. 1998). The gene lying within this locus has the symbol TCF4. |
Transcription
factor |
Activated
by beta catenin CTNNB1 (Kolligs
et al. 2002;Zhai et al. 2002) a
target of GSK3B. Controls TH expression (Yoon
and Chikaraishi 1994) |
Stanley
consortium Combined analysis: Downregulated (Higgs
et al. 2006) |
|
PDLIM5 PDZ
and LIM domain 5: (enigma
homolog; enigma-like LIM domain protein) OMIM 605904 GeneCard 4q22 |
Associated with bipolar disorder in a Japanese case study (Kato et al. 2005) |
Acts
as a cytoplasmic retention factor for ID2 (inhibitor
of DNA binding 2) a growth inhibitory gene that prevents the action
of basic loop helix transcription factors by retaining them in the
cytosol (Lasorella
and Iavarone 2006) |
ID2 is
an inhibitor of basic helix-loop-helix transcription factors, including TCF4 (Langlands
et al. 1997) |
Decreased
expression in prefrontal cortex and lymphocytes (Iwamoto
et al. 2004) |
| VAV3 vav 3 oncogene OMIM GeneCard | Genome-wide association study Baum et al, 2007 | Interacts with tyrosine kinase receptors whose activation phosphorylates VAV3 leading to its association with the receptor Zeng et al, 2000. Phosphatidylinositol 3,4,5-trisphosphate accumulation (product of PIP5K2A) recruits Vav2 and Vav3 which activate RAC1 pathways initiating neurite outgrowth in PC12 cells Aoki et al, 2005 | ||
|
Genes
whose products affect BDNF expression or release |
Increase:
NMDA receptors (GRIN1, GRIN2A, GRIN2B) (Marini
et al. 1998); DRD1 and
DRD2 receptor activation (Fang
et al. 2003) (Kuppers
and Beyer 2001) DRD2 (Takeuchi
et al. 2002), GABA
receptor activation (GABRA1/GABRA5)(Development) (Marty
et al. 1996;Berninger et al. 1995).
The GRM3/GRM5 (Lee
et al. 2006b);
HTR2A receptor
activation (Meller
et al. 2002). HTR2A receptor
stimulation (Vaidya
et al. 1997;Vaidya et al. 1999); TNF (Meeuwsen
et al. 2003;Bayas et al. 2002) Inhibit: IL1B (Barrientos
et al. 2004), GABA
receptor activation (GABRA1, GABRA5) (Adult) (Zafra
et al. 1991). |
|||
|
Genes
associated with bipolar disorder |
Association
studies |
Primary
role |
Links
to other Bipolar genes |
Expression
changes |
| PTPRB protein tyrosine phosphatase, receptor type, B GeneCard | Genome-wide association study Baum et al, 2007 | |||
| PTPRE protein tyrosine phosphatase, receptor type, E GeneCard | WGA Wellcome Trust Case Control Consortium | |||
| PTPRG protein tyrosine phosphatase, receptor type, G GeneCard | Genome-wide association study Baum et al, 2007 AND WGA Wellcome Trust Case Control Consortium | |||
| PTPRN2 protein tyrosine phosphatase, receptor type, N polypeptide 2 GeneCard | Genome-wide association study Baum et al, 2007 |
Table 3:
Glutamatergic neurotransmission, receptors and signaling
|
Genes associated
with bipolar disorder |
Association
studies |
Primary role |
Links to other
Bipolar genes |
Expression
changes |
|
DAOD-amino
acid oxidase OMIM
124050 GeneCard 12q24 Described as a susceptibility locus in
Quebec (Shink et al. 2005) : 12q23-24
region linked to Bipolar disorder in
UK studies (Glaser et al.
2005b) |
Suggestive association in Askenazi Jewish case-parent trios (Fallin et al. 2005). Associated in a german case study (Schumacher et al. 2004) |