AKT1 GeneCard

v-akt murine thymoma viral oncogene homolog 1

14q32.32
14q32 suggested as a locus for maternally imprinted genes in a European study (Cichon et al. 2001).

Weak evidence for association in a Bipolar pedigree (Toyota et al. 2003).

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 GeneCard

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).

PUBMED

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)

Genome-wide association study Baum et al, 2007

DUSP6 GeneCard

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)

PUBMED

Binds to and inactivates erk1 (MAPK3) and erk2 (MAPK1) (downstream components of growth factor receptor signaling) (Muda et al. 1998).

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Stanley consortium Combined analysis: Downregulated (Higgs et al. 2006)

FAT FAT tumor suppressor homolog 1 GeneCard

4q35: Identified as a susceptibility locus in American (NIMH) and Australian studies (Willour et al. 2003;Blair et al. 2002)

 Association reported in an Australian case and family study (Blair et al. 2006)

PUBMED

Cell-cell adhesion cadherin involved in cell migration Binds to ENAH, VASP and MENA (Moeller et al. 2004). Binds to HOMER1 and HOMER3 scaffolding proteins for GRM1 and GRM5

Schreiner et al, 2006

Binds to beta catenin (Cox et al. 2000) CCNTB1 a downstream target of GSK3B Provost et al, 2005 Beta catenin activates TCF4  (Kolligs et al. 2002;Zhai et al. 2002) 

Stanley consortium Combined analysis: Unchanged (Higgs et al. 2006)

GSK3B

Glycogen synthase kinase 3 beta GeneCard

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)

PUBMED

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).

PUBMED

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 GeneCard

20q13.3: Suggested as a susceptibility locus in an American study (Park et al. 2004)

Association reported in a French study (Borsotto et al. 2006)

PUBMED

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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 GeneCard

4p16.1

Region linked to bipolar disorder in several studies (Berrettini 2001;Craddock and Jones 1999;Ewald et al. 1998)

Association reported in a French study (Borsotto et al. 2006)

PUBMED

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).

PUBMED

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. GeneCard

High incidence of Bipolar disorder in 22q11 deletion syndrome  (Papolos et al. 1996)

Suggestive association in an American study (Saito et al. 2003)

PUBMED

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 Phospholipase c Gamma 1 GeneCard

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)

PUBMED

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)

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)

PUBMED

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

OMIM  602516 GeneCard
1q23.3

See Review of genome scan studies (Levinson 2005)

Suggestive association in a Brazilian study (Cordeiro et al. 2005)

PUBMED

GTPase-activating protein

GTPase activating property is inhibited by phosphatidylinositol 3,4,5-trisphosphate, the product of PIP5K2A (Ishii et al. 2005).
Binds to the NRG1 receptor ERBB3(Thaminy et al. 2003). Upregulated by DRD2 receptor agonist and DRD1 receptor antagonist in rat striatum (Taymans et al. 2003).

Stanley consortium Combined analysis: Downregulated (Higgs et al. 2006)

Involved in the transduction of growth factor to MAPK signaling Rodriguez-Viciana et al, 2006

SYNJ1 Synaptojanin 1 GeneCard

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).

PUBMED

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 transcription factor 4

(E2-2, ITF2, SEF2, SEF2-1, SEF2-1A, SEF2-1B) 18q21.1 GeneCard

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.

PUBMED

Transcription factor controlling immunoglobulin and SSTR2 expression.

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)

PUBMED

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)

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

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)

PUBMED