For genome wide association study see Baum et al, 2008 A2BP1, ABCA6, ABCB11, ABTB1, ANK3, ASTN2, AQP4, BMP6, BRE, c11orf44, C14orf143, C20orf17, C21orf127, CAMK2D, CDH20, CHES1, CNTNAP5, CNTN5, CNTN6, CSMD1, CYP4V2, DGKH, DDX42, DFNB31, DOCK3, EDA, EFNA5, FALZ, FLJ39058, FZD2, GAB2, GALNTL4, GASP, GPR51, GRM1, HK2, JAM3, KCTD8, KLF12, KRN1, LAMA3, LDB2, LLGL2, LRCH1, LY86, MAK, MGC42174, MUC2, NCL, NGL1, NYD-SP26, NXN, OR51F2, PAX7, PHF17, PLA2R1, PLCG2, PLSCR4, PSMF1, PTGIS, PTPRB, PTPRG, PTPRN2, RBMS3, RFC3, RGS17, RNPEPL1, RYR2, SDC2, SGCD, SHOC2, SLC26A7, SLC39A3, SLIT3, SNX27, SKIV2L, SRP54, STAB1, SORCS2, SUPT4H1, TCF7L1, TDP1, TEC, UNQ689, VAV3, VPRBP, VGCNL1:

The Wellcome Trust Case Control Consortium. Genome-wide association study.The following genes are those corresponding to the rs SNP numbers defined in the supplementary material of this paper (moderate to strong association) AOF1  AK3L2  AKAP10 C14orf58  CAPN6  CDC25B CMTM8  CSF2RB  DFNB31(see above) DPP10  ESRRG  FAM126A  GABRB1 GRM7 KLHDC1 LAMP3 LOC283547  LOC731264 LRRC7 PALB2 PAX5 PTPRE  (PTPRG RNPEPL1 see above) SOX5 SVEP1 SYK SYN3 SYNE1 TDRD9 THRB THSD7A  TRDN   ZBTB44 ZNF274 ZNF490 ZNF659  ZNF678 

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).

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)

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 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)

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)

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 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)

- 

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)

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. GeneCard

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 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)

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)

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)

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).

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.

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)

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)

DAO is responsible for the catabolism of D-amino acids including D-serine (Nagata 1992), an endogeous glycine-site ligand for the NMDA receptor (Mothet et al. 2000).

DAO catabolises D-serine (Nagata 1992) a ligand for the NMDA receptor (Mothet et al. 2000) (GRIN1, GRIN2A, GRIN2B)

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

DAOA GeneCard

D-amino acid oxidase activatorOMIM 607408 13q34

 Susceptibility locus (Craddock et al. 2005)

D-amino acid oxidase (DAO) and an activator protein (DAOA, initially described as G72) are both associated with schizophrenia (Chumakov et al. 2002) and DAOA has also been linked with bipolar disorder (Chen et al. 2004;Addington et al. 2004;Hattori et al. 2003).

D-amino acid oxidase

Activates DAO

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

GRID1 glutamate receptor, ionotropic, delta 1 GeneCard
 10q22;Bipolar susceptibility locus (See meta-analysis) (Levinson 2005)

Associated with Bipolar disorder in a study of Ashenazi Case-parent trios (Fallin et al. 2005)

Glutamate receptor

 -

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

GRIK4 Kainate receptor

OMIM 600282 GeneCard

Association reported for both schizophrenia and bipolar disorder in a scottish case study (Pickard et al. 2006)

High-affinity Kainate receptor

 -

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

GRIN1

(NMDA receptor subunit NR1)

OMIM 138249 GeneCard 9q34.3

Region linked to early onset bipolar disorder (Faraone et al. 2006)

Polymorphisms in the GRIN1 promoter (Mundo et al. 2003)  have  been associated with bipolar disorder.

NMDA/bipolar disorder

Trophic concentrations of NMDA stimulate the PI3kinase/AKT signaling cascade (Zhu et al. 2002;Lafon-Cazal et al. 2002),  (Perkinton et al. 2002)  (Manabe and Lipton 2003) and stimulate BDNF expression (Marini et al. 1998).

Toxic concentrations of NMDA phosphorylate and inactivate AKT1 and decrease the phosphorylation of GSK3B (Luo et al. 2003); Binds to DRD1 (Fiorentini et al. 2003) Favaron et al. 1993). Oligodendrocytes express GRIN1 and activation of NMDA receptors in these cells increases their expression of polysialylated NCAM1 that is required for oligodendrocyte migration (Wang et al. 1996). Expression regulated by BDNF (Schratt et al. 2004)

RNA downregulated in dorsolateral prefrontal cortex (Nakatani et al. 2006). No change in protein expression on orbitofrontal cortex or dentate hilus.(Toro and Deakin 2005)

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

GRIN2A NMDA receptor subunit NR2A

OMIM 138253 GeneCard

16p13.2 Region linked to Bipolar disorder in a Genome-wide linkage scan (NIMH) (Cheng et al. 2006)

Polymorphisms in the GRIN2A promoter (Itokawa et al. 2003) have been associated with bipolar disorder.

Glutamate

PLCG1 is directly coupled to GRIN2A (Gurd and Bissoon 1997a). Expresion regulated by BDNF (Margottil and Domenici 2003).

No change in anterior cingulate cortex. (Woo et al. 2004).

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

GRIN2B NMDA receptor subunit NR2B

OMIM 138252 12p12 GeneCard

 (Martucci et al. 2006)

Binds to PLCG1 (Gurd and Bissoon 1997b); BDNF activates NMDA receptors via a GRIN2B dependent mechanism (Levine and Kolb 2000)

No change in expression (Martucci et al. 2006)

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

CIT citron (rho-interacting, serine/threonine kinase 21) GeneCard

12q24 12q23-24 region linked to Bipolar disorder in  UK studies (Glaser et al. 2005b)

Association reported in an American study (Lyons-Warren et al. 2005)

Plays a role in cytokinesis and in the control of dendritic morphology  (Di Cunto et al. 2003)

Binds to GRIN1 and is a component of the NMDA receptor adhesion complex (Husi et al. 2000). Binds to DISC1 (Ozeki et al. 2003)

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

DISC1

Disrupted in schizophrenia 1

OMIM 605210 GeneCard

1q42.1

1q42 described a s a susceptibility locus in a Scottish study (Macgregor et al. 2004)

Association reported in an American study (Hodgkinson et al. 2004) and an American family study (Maeda et al. 2006).

Involved in neurite outgrowth and cortical development.
Also binds to ATF4 and ATF5 transcription factors.  (Millar et al., 2003) . ATF4 binds to nrf1 and nrf2 (NFE2L1 and NFE2L2 ) . NFE2L2 controls the transcription of genes related to glutathione/ quinone oxidative stress  (Chanas et al, 2002) . NFE2L2 controls the expression of BDNF, in neurones (Lee et al, 2003) and of GABRA1 and G6PD astrocytes (Lee et al, 2003). NFE2L1 controls the expression of TNF Novotny et al, 1998

Binds to CIT (Ozeki et al. 2003) , MLC1 (Millar et al. 2003) and DPYSL2 (Camargo et al, 2006). Binding partner ATF4 is involved in endoplasmic reticulum stress and controls GCH1 transcription (Kapatos et al. 2000). Binds to elements of the glutamate receptor scaffold (see (Carter 2006)) and TENC1 (Millar et al. 2003)a negative regulator of PI3K/AKT signalling (Hafizi et al. 2005). Binding partner MGAT3 is involved in N-glycans biosythesis, as is ALG9 . Binds to growth factor receptor bound protein 2 GRB2 a key component of growth factor signalling Shinoda et al, 2007

ATF4 controls the expression of ATF3, CHOP (DDIT3), GADD34 (PPP1R15A) and HERPUD1 Wek et al, 2006 Ma and Hendershot,2004

Decreased mRNA expression in lymphoblasts; Correlated with manic symptomatology (Maeda et al. 2006) .

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

NOS1
Nitric oxide synthase
OMIM 163731 GeneCard
12q16
?

Weakly Associated in a study of Ashkenazi case-parent  trios (Fallin et al. 2005)

Nitric oxide synthesis

Neuronal nitric oxide synthase stimulated by NMDA receptor activation

Increased expression in hippocampus (Benes et al. 2006)

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

NOSIAP (CAPON) 

OMIM 605551 GeneCard

1q23.3

Region linked to bipolar disorder  (Levinson 2005)

Suggested implication based on the identification of a variant with increased expression (Xu et al. 2005a)

Nitric oxide synthesis

Binds to NOS1

Increased expression in both schizophrenia and bipolar disorder (dorsolateral prefrontal cortex) correlated with genotype (Xu et al. 2005a). Stanley consortium Combined analysis: Unchanged (Higgs et al. 2006)

NOS3

Endothelial nitric oxide synthase

7q36 GeneCard

Region linked to Bipolar disorder in a European study (Etain et al. 2006)

Associated with bipolar disorder in a german study (Reif et al. 2005).

Endothelial Nitric oxide synthase

Phosphorylated by AKT1 (Wu 2002).  Nitric oxide affects AKT1, SLC6A3, SLC6A4, GRIN2A, GRIN2B, HTR2A and TH function (Yasukawa et al. 2005) (Nozik-Grayck et al. 2002)  (Choi et al. 2000).(Kuhn and Geddes 2003;Park et al. 2002)(Bryan-Lluka et al. 2004;Mishra et al. 2002). NOS3 knockout decreases cerebral BDNF expression  (Chen et al. 2005)

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

GRM3 Metabotropic glutamate receptor mgluR3 OMIM 601115

GeneCard 7q21.1-q21.2

Region linked to Bipolar disorder in a Genome-wide linkage scan (NIMH) (Cheng et al. 2006)

 Association reported in a case-parent trio study in Askemazi Jews (Fallin et al. 2005)

 -

MGlur2/3 antagonism suppresses stress-induced increases in frontal cortex BDNF expresion (Lee et al. 2006b)

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

GRM4 Metabotropic glutamate receptor mgluR4 

OMIM 604100 GeneCard
6p21.3 ?

 Association reported in a case-parent trio study in Askemazi Jews (Fallin et al. 2005)

Metabotropic glutamate receptor

 -

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

Genes associated with bipolar disorder

Association studies

Primary role

Links to other Bipolar genes

Expression changes

CCL2 chemokine (C-C motif) ligand 2 (MCP1) GeneCard

17q11.2-q12 Region linked to bipolar disorder (see review of genome scans (Levinson 2005))

A polymorphism in this gene was shown to influence the symptomatology of bipolar disorder in a Korean population (Pae et al. 2004a).

Chemokine

Stimulates the PI3K/AKT pathway (Jones et al. 2003) (Selzman et al. 2002).

TNF upregulates CCL2 expression (Murao et al. 2000)

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

IL1B Interleukin 1B OMIM 147720 GeneCard

2q14: Susceptibility locus in a European study of early onset Bipolar disorder (Etain et al. 2006)

Association reported in a Spanish study (Papiol et al. 2004)

Cytokine

Activates PKR (EIF2AK2) Williams, 2001

BDNF stimulates IL1B secretion from macrophages (Asami et al. 2006). IL1B suppresses the learning-associated increases in hippocampal BDNF expression (Barrientos et al. 2004)

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

IL1RN Interleukin 1 receptor antagonist
OMIM 147679 GeneCard
Susceptibility locus in a European study of early onset Bipolar disorder 2q14.2  (Etain et al. 2006)

Association reported in a Spanish study (Papiol et al. 2004)

IL1B inhibitor

Social isolation decreases hippocampal BDNF mRNA, an effect blocked by IL1RN infusion (Barrientos et al. 2003)

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

IL2RB Interleukin 2 receptor beta chain GeneCard

22q13.1

 Region linked to bipolar disorder (see review of genome scans (Levinson 2005))

Association reported in a case-parent trio study in Askenazi Jews (Fallin et al. 2005)

IL2 receptor

IL-2 Activates the PI3K pathway in T cells and myelin (Benczik and Gaffen 2004). Associated with phosphoinosite kinase PIK3R1 (Migone et al. 1998;Chakraborty et al. 2003)

Increased levels of serum IL2 receptors often reported in bipolar disorder  (Tsai et al. 2003).

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

TNFA: Tumor necrosis factor alpha OMIM 191160 GeneCard

6p21.3

Folate-sensitive fragile site(Tastemir et al, 2006)

A polymorphism in this gene has been associated with both bipolar disorder and major depression in a Korean population (Pae et al. 2004b;Jun et al. 2003)

Cytokine

Activates PKR (EIF2AK2) Williams, 2001

Stimulates the PI3K/AKT pathway (Marchetti et al. 2004). Inhibits AKT1 activity by increasing the production of C2 ceramide which maintains AKT1 in a dephosphorylated active state (Teruel et al. 2001). Stimulates the expression of BDNF and CCL2 in human astrocytes (Meeuwsen et al. 2003) and of GCH1 in C6 glioma cells (D'Sa et al. 1996).Both TNF and IL1B stimulate the activity of the brain serotonin transporter SLC6A4 via p38 mitogen-activated protein kinase  activation (Zhu et al. 2006)

Increased expression in hippocampus (Benes et al. 2006)

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

Genes associated with bipolar disorder

Association studies

Primary role

Links to other Bipolar genes

Expression changes

GCH1

GTP cyclohydrolase 1 (dopa-responsive dystonia) 14q22.1-q22.2 GeneCard

Region linked to Bipolar disorder (Kealey et al. 2005)

Associated with bipolar disorder in an Irish study (Kealey et al. 2005).

Tetrahydrobiopterin synthesis

Stimulated by growth factors via the PI3 kinase pathway (Bauer et al. 2002). Tetrahydrobiopterin is a cofactor for TH TPH and NOS3: regulated by TNFA (D'Sa et al. 1996)and ATF4(Kapatos et al. 2000), binding partner of DISC1(Stegenga et al. 1996;Hirayama and Kapatos 1995)

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

G6PD

glucose-6-phosphate dehydrogenase

Xq28 GeneCard

OMIM MAFD2

Association reported in Italian studies (Bocchetta 2003;Bocchetta et al. 1999).

D-glucose 6-phosphate + NADP+ = D-glucono-1,5-lactone 6-phosphate +
NADPH + H+.

The NADPH so formed plays and important role in the maintenance of reduced glutathione (Fujii 1995).

Expression stimulated by growth factors (Stanton et al. 1991).

PDGF results in the rapid release of G6PD that is attenuated by PI3K or PLCG1 inhibition (Tian et al. 1994). G6PD expression is controlled by sterol regulatory element binding protein  SREBp1a (Amemiya-Kudo et al. 2002) whose transcription is in turn controlled by AKT1 (Porstmann et al. 2005).

G6PD deficiency has been associated with Bipolar disorder (Bocchetta 2003;Bocchetta et al. 1999)

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

SLC25A4 (ANT1)

Adenine nucleotide translocator

4q35 GeneCard

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

An ANT1 mutation associated with Bipolar disorder has been described in a family with dominantly inherited progressive external ophthalmoplegia  (Siciliano et al. 2003).

Mitochondrial Adenine nucleotide translocator

Binds to BAX and modifies the mitochondrial permeability transition pore complex contributing to increased mitochondrial permeability and cell death (Marzo et al. 1998)

Activated by serotonin (HTR2B) receptor stimulation via the PI3K/AKT pathway (Nebigil et al. 2003).

Facilitates glutamate transport (Buck et al. 2003)

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

SST

Somatostatin

3q28 GeneCard

?

Weak association reported in a Japanese study (Nakatani et al. 2006)

-

Activates SSTR5. Expression synthesis or release promoted by BDNF in hypothalamic, cortical and hippocampal neurones (Givalois et al. 2006;Villuendas et al. 2001;Marty and Onteniente 1999). In SH-SY5Y human neuroblastoma cells, which express all SSTR isoforms, somatostatin inhibits erk1/2 and RAC activity and indirectly suppresses the PDGF-activated PI3 kinase pathway via inhibition of RAC, a downstream target of the PI3 kinase (Pola et al. 2003).  Somatostatin is generally antiproliferative.

RNA downregulated in dorsolateral prefrontal cortex (Nakatani et al. 2006)

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

SSTR5

Somatostatin receptor 5

16p13.3 GeneCard Region linked to Bipolar disorder in a Genome-wide linkage scan (NIMH) (Cheng et al. 2006)

Polymorphisms in the gene coding for this receptor are associated with bipolar disorder (Nyegaard et al. 2002).

Growth suppressive

Forms heterodimers with DRD2 (Rocheville et al. 2000)

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

DPYSL2

dihydropyrimidinase-like 2 OMIM 602463 GeneCard
  (collapsin response mediator protein CRMP2)
8p22-p21

Bipolar locus (see meta-analysis review) (Levinson 2005)

Weakly Associated in a study of Ashkenazi case-parent  trios (Fallin et al. 2005)

Involved in axonal outgrowth. 

Phosphorylated by GSK3B (Yoshimura et al. 2005). Binds toDISC1 (Camargo et al, 2006). NMDA receptor activation results in increased calpain cleavage of DPYSL2 and the resulting product reduces the surface expression of the NMDA receptor subunit GRIN2B (Bretin et al, 2006)

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

Genes associated with bipolar disorder

Association studies

Primary role

Links to other Bipolar genes

Expression changes

ALOX12 arachidonate 12-lipoxygenase

17p13.1 GeneCard

Region linked to bipolar disorder (see review of genome scans (Levinson 2005))

An ALOX12 polymorphism associates with Bipolar disorder in a Brazilian population (Fridman et al. 2003).

Arachidonate metabolism

Arachidonate + O2 -> 12(S)HPETE

12(S) HETE activates the AKT1 pathway in epidermal cancer cells (Szekeres et al. 2002) and in prostate cancer cells (Pidgeon et al. 2002) and is also linked to stimulation of PI3 kinase (Szekeres et al. 2000;Szekeres et al. 2002). Stimulated by AGT) (Zhu et al. 2000),NMDA receptor activation (GRIN1, GRIN2A) and noradrenaline (Wolfe et al. 1990). ALOX12 inhibition prevents oligodendrocyte cell death induced by glutathione inhibition (Wang et al. 2004).

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

AGT Angiotensinogen

1q42-q43 GeneCard 1q42 identified as a susceptibility locus in a Scottish study (Macgregor et al. 2004)

Associated with Bipolar disorder in a Brazilian population (Meira-Lima et al. 2000).

Cleaved by renin to Angiotensin I which is cleaved by ACE to Angiotensin II

Angiotensin stimulates AKT1 activity and promotes neurite extension in hypothalamic neurones (Yang et al. 2002).

PLCG1 is stimulated by angiotensin II (AGT) in smooth muscle cells (Marrero et al. 1994). Stimulates TH expression (Kim et al. 1996).

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

APOE

Apolipoprotein E OMIM 107741 GeneCard

19q13.2

Region linked to bipolar disorder (see review of genome scans (Levinson 2005))

Early onset bipolar disorder patients possess an increased frequency of the APOE4 allele (Bellivier et al. 1997).

Cholesterol transport

APOE activates the PI3K/AKT pathway in neuro2A cells (Laffont et al. 2002). APOE 3 and APOE4 also acutely activate GSK3B in human SH-SY5Y neuroblastoma cells and APOE4 subsequently inactivates GSK3B. APOE4 also stimulated AKT1 activity in these cells (Cedazo-Minguez et al. 2003). Apolipoprotein E4 also inhibits phosphatidylinositol 4-kinase (PI4K) and phosphatidylinositol 4-phosphate 5-kinase (PIP5K) activity in the rat cerebral cortex (Zambrzycka and Kacprzak 2003). The isoforms were not specified.Activates GSK3B (Cedazo-Minguez et al. 2003)

Increased protein levels in the caudate putamen and brodmann area 9 , decreased levels  in Brodmann Area 10.(Digney et al. 2005).

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

CALCA calcitonin/calcitonin-related polypeptide, alpha
11p15.2-p15.1 GeneCard
Identified as a linkage region in an American study (NIMH) (McInnis et al. 2003)

A polymorphism in this gene has been associated with bipolar disorder in a Swedish study (Buervenich et al. 2001).

Stimulates PI3K/AKT signaling (Parameswaran et al. 2000)

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

CHRNA7 Nicotinic receptor alpha 7 subunit OMIM 118511 GeneCard

15q14 Region linked to bipolar disorder (Reif et al. 2004;Turecki et al. 2001)

Association reported in a Taiwanese study (Hong et al. 2004)

Nicotinic receptor

Binds to the P85 subunit of phosphatidylinositol 3-kinase (PIK3R1). Nicotine stimulation results in AKT1 phosphorylation (Kihara et al. 2001).

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

DTNBP1 Dysbindin

OMIM 607145 GeneCard

6p22.3
6p22.2 linked to bipolar disorder in an American study (Schulze et al. 2004)

Associated with bipolar disorder in subset of psychotic patients (Raybould et al. 2005). Weakly Associated in a study of Ashkenazi case-parent  trios (Fallin et al. 2005)

Overexpression reduces glutamate release (Numakawa et al. 2004)

Dysbindin overexpression in primary cortical neurones increases AKT1 phosphorylation and protects neurones via stimulation of the PI3K/AKT cascade (Numakawa et al. 2004)

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

P2RX7 purinergic receptor P2X, ligand-gated ion channel, 7 12q24 GeneCard

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)

Association suggested in a Canadian Case study (Barden et al. 2006)

Purinergic receptor forming a pore/channel.

Phosphorylated by ADRBK2 (Feng et al. 2005). Stimulates AKT phosphorylation in astrocytes via diverse routes (Jacques-Silva et al. 2004). Astrocytic receptors control glutamate release(Duan et al. 2003). IL1B increases astrocytic P2RX7 expression and P2RX7 stimulation increases IL1B release (Narcisse et al. 2005)

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

Genes associated with bipolar disorder

Association studies

Primary role

Links to other Bipolar genes

Expression changes

NCAM1 Neural cell adhesion  molecule 1

11q23.1 ? GeneCard

An NCAM1 polymorphism is associated with Bipolar disorder in the Japanese population (Arai et al. 2004).

NCAM1 is a neural adhesion molecule and is its own neuronal receptor and substrate ligand. NCAM1/NCAM1 binding stimulates axonal growth and neuritic sprouting. This effect is mediated via interaction with tyrosine kinase receptors, which are activated by NCAM1 mediated adhesion.

Stimulates PI3K/AKT signaling via FGFR1 interactions (Kiselyov et al. 2003). TrkB phosphorylation and BDNF signaling is impaired in NCAM knockout mice. Polysialylated-NCAM interacts with BDNF (Vutskits et al. 2001). Oligodendrocytes express GRIN1 and activation of NMDA receptors in these cells increases their expression of polysialylated NCAM1 that is required for oligodendrocyte migration (Wang et al. 1996).

Increased protein expression of a splice variant (NCAM-VASE) in the hippocampus (Vawter et al. 1998).

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

Genes associated with bipolar disorder

Association studies

Primary role

Links to other Bipolar genes

Expression changes

ALG9 asparagine-linked glycosylation 9 homolog GeneCard 11q23 ? A mutation in this gene is responsible for congenital disorder of glycosylation Type 1L (Frank et al. 2004b)

Disrupted by a translocation breakpoint segregating with Bipolar disorder in a small family (Baysal et al. 2002)

A deficiency of ALG9 causes an accumulation of lipid-linked-GlcNAc (2) Man (6) and -GlcNAc(2)Man(8) containing structures and defects in N-glycosylation (Frank et al. 2004b).(GlcNac = N-acetylglucoseamine; Man = mannose)  This enzyme is involved in glycosylation, a post-translational protein modification involving a multitude of targets.  The N-linked glycosylation pathway necessitates the assembly of an oligosaccharide core with a dolichylpyrophosphate lipid carrier and the transfer of this assembly to nascent polypeptide chains. ALG9 is involved in this assembly (Frank et al. 2004b).

Glycosylation is involved in protein folding and processing. Defects in type 1 glycosylation are associated with increased endoplasmic reticulum stress(Lecca et al. 2005;Freeze 2002;Shang et al. 2002). Deletion in yeast results in the hypoglycosylation of secreted proteins (Burda et al. 1996).

-

HIP1R huntingtin interacting protein 1 related GeneCard

12q24

12q23-24 region linked to Bipolar disorder in  UK studies (Glaser et al. 2005b)

This gene was isolated from Bipolar pedigrees showing decreased age of onset with successive generations (Provencal et al. 2004).

Actin and phospholipid binding protein: Plays a role in growth factor receptor trafficking (Hyun et al. 2004).

Binds to phosphatidylinositol 3,4-bisphosphate the product of PIP5K2A and phosphatidylinositol 3,5-bisphosphate  (Hyun et al. 2004) a product of PIP5K3 (Ikonomov et al. 2002). Binds to dynein light chain (DYNLL1) a protein involved in intracellular transport. DYNLL1 also binds to and inhibits the activity of NOS1 (Jaffrey and Snyder 1996)and to the BDNF receptor NTRK2 (Yano et al. 2001)

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

HSPA5 heat shock 70kDa protein 5 (glucose-regulated protein, 78kDa) (GRP78 or BIP) GeneCard

9q33-q34.1

9q34 described as a locus for early onset Bipolar disorder (Faraone et al. 2006)

Association observed in Japanese case and family study (Kakiuchi et al. 2005)

Folding and assembly of proteins in the endoplasmic reticulum.

Binds to three key proteins involved in ER stress response.  (PERK (Gene symbol = EIF2AK3), IRE1 alpha (gene symbol ERN1) and the transcription factor ATF6) and its saturation by unfolded proteins releases these stress response activators (Xu et al. 2005b).  ATF6 controls the expression of XBP1 which is spliced by IRE1 alpha to produce a highly active transcription factor (Yoshida et al. 2001;Lee et al. 2002)Also functions as a cell-surface receptor for activated alpha-2 macroglobulin (A2M) involved in the activation of Ras and PI3K signal transduction (Misra et al. 2004). Activation of this receptor increases PLCG1 phosphorylation in macrophages (Misra et al. 1995).

No change in protein levels in temporal cortex (Bown et al. 2000).

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

KIF13A kinesin family member 13A GeneCard

6p23 ?

Weakly Associated in a study of Ashkenazi case-parent  trios (Fallin et al. 2005)

Motor protein transporting the mannose-6-phosphate receptor (Nakagawa et al. 2000)

-

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

NAPG N-ethylmaleimide-sensitive factor attachment protein, gamma. Gamma SNAP GeneCard

18p11.22 . 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)

Association reported in an American case study (Weller et al. 2006)

Play a role in intracellular membrane fusion and vesicular trafficking

-

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

SYBL1 Synaptobrevin-like 1 (VAMP7, VAMP-7, TI-VAMP)

Xq28 and Yq12

OMIM MAFD2

Association reported in a German population and in male Americans (Muller et al. 2002;Saito et al. 2000)

In PC12 cells SYBL1 mediates the vesicular transport from endosomes to lysosomes and thus assists in the breakdown of endocytosed protein products. An antibody to SYBL1 inhibits the breakdown of EGF (Advani et al. 1999) in PC12 cells. SYBL1 is thus likely to participate in the breakdown of a large number of endocytosed macromolecules including other growth factors that are processed in this way. SYBL1 also plays a role in neurite and dendrite  outgrowth in PC12 cells and hippocampal neurones (Martinez-Arca et al. 2000, 2001)

- -

RNA upregulated in dorsolateral prefrontal cortex (Nakatani et al. 2006).

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

WFS1 Wolfram syndrome 1 (wolframin) GeneCard

4p16: Described as a locus for pscychosis/suicidal behaviour in Bipolar disorder (Cheng et al. 2006)

Polymorphisms in this gene have been associated with both bipolar disorder and major depression (Koido et al. 2004;Furlong et al. 1999).

 -

Endoplasmic reticulum cation channel activated by inositol 1,4,5 triphosphate, the product of PLCG1 (Osman et al. 2003). Transcription controlled by XBP1 (Kakiuchi et al. 2006).

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

XBP1 X-box binding protein 1. OMIM 194355 GeneCard

22q12

OMIM MAFD1

Association reported in Japan and Taiwan (Hou et al. 2004;Kakiuchi et al. 2003)

ER stress

Regulates WFS1 transcription (Kakiuchi et al. 2006). Controls expression of DNAJC3 (p58IPK), DNAJB9 (ERDJ4), DNAJB11 (HEDJ),  EDEM.protein disulfide isomerase-P5 and SERP1 (RAMP4) (Lee at al, 2003).

RNA upregulated in dorsolateral prefrontal cortex (Nakatani et al. 2006). In lymphoblastoid cells, XBP1-dependent transcription activity of the Bipolar associated allele was reduced and in the cells with this allele, induction of XBP1 expression after ER stress was markedly reduced. Valproate, one of three mood stabilizers, rescued the impaired response by inducing ATF6, the controller of XBP1(Kakiuchi et al. 2003). Stanley consortium Combined analysis: Unchanged (Higgs et al. 2006)

Genes associated with bipolar disorder

Association studies

Primary role

Links to other Bipolar genes

Expression changes

ARNTL aryl hydrocarbon receptor nuclear translocator-like GeneCard

11p15. Identified as a linkage region in an American study (NIMH) (McInnis et al. 2003)

Association reported in two American studies (Nievergelt et al. 2006) (Mansour et al. 2006).

Circadian rhythm

Forms heterodimer with CLOCK.

RNA upregulated in dorsolateral prefrontal cortex (Nakatani et al. 2006).

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

PER3 period homolog 3 GeneCard

1p36.23 Region linked to bipolar disorder (see review of genome scans (Levinson 2005))

Association reported in an American study (Nievergelt et al. 2006).

Circadian rhythm

-

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

CLOCK GeneCard

4q12

Region linked toBipolar disorder in UK Irish Sib-pair Genome screen  (Lambert et al. 2005)

CLOCK has been associated with the recurrence of Bipolar depression in one study (Benedetti et al. 2003) see also Shi et al 2008

Circadian rhythm

Forms heterodimer with ARNTL.

GSK3B controls elements in the circadian cycle (Harms et al. 2003) .Controls ATF4 (a binding partner of DISC1) Igarashi et al, 2007

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

GPR50 Orphan receptor GeneCard

Xq28

OMIM MAFD2

This receptor has been associated with Bipolar disorder and major depression particularly in women (Thomson et al. 2004).

Dimerises with melatonin receptors MT1 and MT2 and inhibits activity of MT1 (Levoye et al. 2006)

Melatonin plays a key role in circadian control. Activation of the AKT pathway has been implicated in the neuroprotective effects of melatonin in stroke models (Kilic et al. 2005)

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

RFX4 regulatory factor X, 4 GeneCard

12q24

12q23-24 region linked to Bipolar disorder in  UK studies (Glaser et al. 2005b)

Association reported in a British study (Glaser et al. 2005a)

Associated with two other similar transcription factors RFX2 and RFX3: Light-induced and localised in the suprachiasmatic nucleus (Araki et al. 2004). Involved in cortical development in mice (Zarbalis et al. 2004).

 -

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

TIMELESS 12q12-q13 GeneCard

?

Weak association reported in an American study (Mansour et al. 2006)

 -

Phosphorylated by GSK3B (Iitaka et al. 2005)

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

Genes associated with bipolar disorder

Association studies

Primary role

Links to other Bipolar genes

Expression changes

MTND1 ND4 NADH dehydrogenase subunit 4 OMIM OMIM GeneCard

Mitochondrial DNA

Mutation leading to reduced activity observed in a Japanese population -(Munakata et al. 2004)

Subunit of Mitochondrial complex 1

- 

-

NDUFV2 NADH dehydrogenase (ubiquinone) flavoprotein 2, 24kDa GeneCard

18p11.31-p11.2

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)

NDUFV2 polymorphisms are associated with Bipolar disorder and schizophrenia in Japanese and American populations (Washizuka et al. 2004;Washizuka et al. 2003)

Subunit of Mitochondrial complex 1

-

Increased mRNA expression in DLPFC (Nakatani et al. 2006). Decreasesd expression in lymphoblastoid cell lines isolated from bipolar disorder patients (Washizuka et al. 2005).

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

Genes associated with bipolar disorder

Association studies

Primary role

Links to other Bipolar genes

Expression changes

adcy8

ATP-binding cassette, sub-family B (MDR/TAP), member 1

ATP1A3 ATPase, Na+/K+ transporting, alpha 3 polypeptide GeneCard

19q13.31

Region linked to bipolar disorder (see review of genome scans (Levinson 2005))

A polymorphism in this gene has been associated with bipolar disorder in one study (Mynett-Johnson et al. 1998a).

Sodium/Potassium ATPase

Would indirectly affect most transport activity e.g. serotonin (SLC6A4), and dopamine (SLC6A3) transporters. Sodium potassium ATPase activity is inhibited by 12-HETE, the product of ALOX12 and arachidonic acid mediated inhibition of the renal sodium pump in young rats is attenuated by ALOX12 inhibition (Li et al. 2000).

A meta-analysis of multiple studies suggesting sodium pump dysfunction concluded that lymphocyte activity is decreased in bipolar patients (isoform not specified) (Looney and el Mallakh 1997). Stanley consortium Combined analysis: Unchanged (Higgs et al. 2006)

SLC12A6 GeneCard

Potassium/chloride transporter (ACCPN, DKFZP434D2135, KCC3, KCC3A, KCC3B) 15q13-q15

Association reported in an American case study (Meyer et al. 2005)

Overexpression is growth promoting in fibroblasts (Shen et al. 2001)

Expression is regulated by the nitric oxide/cGMP/Protein kinase G cascade in endothelial cells  (NOS3)(Di Fulvio et al. 2001). Activated by osmotic and oxidative stress (Piechotta et al. 2002)

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

TRPM2 transient receptor potential cation channel, subfamily M, member 221q22.3 GeneCard

Region linked to bipolar disorder (McQuillin et al. 2005)

Association reported in an American study(Xu et al. 2006)

Calcium-permeable cation channel regulated by free intracellular ADP-ribose. The encoded protein is activated by oxidative stress and confers susceptibility to cell death (Kaneko et al. 2006). Also activated by cyclic ADP ribose (Togashi et al. 2006)

Binds to the inositol 1,4,5 triphosphate (PLCG1 product) channel ITPR3 (Tang et al. 2001).

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

Genes associated with bipolar disorder

Association studies

Primary role

Links to other Bipolar genes

Expression changes

COMT Catechol-O-methyltransferase OMIM 116790 22q11.21 GeneCard

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

Several studies have reported association of the low-activity allele of COMT with bipolar disorder (Rotondo et al. 2002;Mynett-Johnson et al. 1998b;Kirov et al. 1998;Li et al. 1997). COMT is a susceptibily gene for both bipolar disorder and schizophrenia (Shifman et al. 2004).

Catalyzes the transfer of a methyl group from S-adenosylmethionine to catecholamines, including dopamine, adrenaline, and noradrenaline, forming 3-methoxytyramine, metanephrine and normetanephrine respectively.

Would affect dopamine metabolism. COMT activation also increases homocysteine synthesis and release from astrocytes (derived from S-adenosylmethionine) (Huang et al. 2005)

No change in dorsolateral profrontal cortex mRNA expression (Tunbridge et al. 2004).

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

DDC DOPA decarboxylase GeneCard

7p11 ?

A Danish study has linked this gene to bipolar disorder (Borglum et al. 2003;Borglum et al. 1999)

DOPA decarboxylase catalyses the formation of dopamine from l-DOPA but can also synthesise 5-HT from 5-hydroxytyptophan, tryptamine from tryptophan, tyramine from tyrosine and phenylethylamine from pheylalanine. It is expressed in both serotoninergic and dopaminergic neurones (Tison et al. 1991) and in astrocytes (Li et al. 1992).

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

DRD1 D1 dopamine receptor GeneCard

5q35.1

5q31-5q35 linked to both schizophrenia and psychosis in bipolar disorder (Sklar et al. 2004)

The dopamine receptors DRD1, DRD2 and DRD3 have each been associated with bipolar disorder (Ni et al. 2002;Massat et al. 2002;Chiaroni et al. 2000;Li et al. 1999;Staner et al. 1998;Manki et al. 1996).

Positively coupled to adenylate cyclase (Kebabian 1997)

Increases neuronal BDNF expression (Fang et al. 2003),(Kuppers and Beyer 2001) : Activates AKT1 (Brami-Cherrier et al. 2002). Activates PLCG1 via PKA (Yu et al. 1996) ; In LTK and HEK293 cells dopamine D1 receptor stimulation (DRD1) decreases PLCG1 cortical membrane expression and activity (Yu et al. 1996).
Binds to GRIN1 (Fiorentini et al. 2003).

Decreased mRNA in hippocampal area CA2 (Pantazopoulos et al. 2004).

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

DRD2 Dopamine receptor OMIM 126450 GeneCard

11q23

-

?

Negatively coupled to adenylate cyclase (Huff 1996)

Stimulates the PI3K/AKT pathway in PC12 or substantia nigra cells via transactivation of the EGF receptor (Nair and Sealfon 2003). In cortical neurones, DRD2 receptor stimulation also protects neurones from the toxic effects of glutamate via the PI3K/AKT pathway (Kihara et al. 2002). Increases BDNF expression in NG108-15 cells (Takeuchi et al. 2002) Activates AKT1 (Brami-Cherrier et al. 2002) Coupled to GNAZ (Obadiah et al. 1999) which links to PLCG1 (Tran et al. 2002). In the mouse striatum amphetamine or Dopamine transporter knockdown inactivate AKT1 and activate GSK3B, effects that are blocked by D2 receptor antagonism or by lithium (Beaulieu et al. 2004).Heterodimerises with SSTR5 (Rocheville et al. 2000).

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

DRD3 Dopamine receptor

OMIM 126451 GeneCard 3q13

Negatively coupled to adenylate cyclase (Kuzhikandathil et al. 2004).

Stimulates the PI3K/AKT pathway via transactivation of the EGF receptor (Beom et al. 2004). Coupled to GNAZ (Obadiah et al. 1999) which links to PLCG1 (Tran et al. 2002). Binds to GRB2 (Oldenhof et al. 2001). BDNF increases the expression of DRD3 in the developing brain and maintains its expression in adulthhood (Guillin et al. 2001;Guillin et al. 2003;Sokoloff et al. 2002)

Decreased expression in lymphocytes (Vogel et al. 2004).

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

SLC6A3 DAT1 dopamine transporter OMIM 126455 GeneCard

5p15.3

5p15 shows suggestive evidence for linkage related to psychosis in bipolar disorder (NIMH) (Cheng et al. 2006)

Two studies have suggested association of the dopamine transporter to bipolar disorder (Greenwood et al. 2001;Waldman et al. 1997)

Dopamine transport

Activity controlled by PI3 kinase pathway (Carvelli et al. 2002). The PI3 kinase pathway controls dopamine uptake in synaptosomes and in appropriately transfected HEK-293 cells. Inhibition of phosphatidylinositol (PI) 3-kinase by LY294002 induces internalization of the human transporter and reduces transport capacity. Insulin, which activates this pathway, stimulated dopamine uptake, an effect also blocked by LY294002. Increased dopamine uptake was also observed in HEK-293 following transfection with constitutively active PI3 kinase (murine PI 3-kinase p110alpha (PIK3CA) (Carvelli et al. 2002). In the mouse striatum amphetamine or Dopamine transporter knockdown inactivate AKT1 and activate GSK3B effects that are blocked by DRD2 receptor antagonism or by lithium (Beaulieu et al. 2004).

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

TH Tyrosine hydroxylase OMIM 191290 GeneCard

11p15.5: Identified as a linkage region in an American study (NIMH) (McInnis et al. 2003)

TH has been weakly associated with bipolar disorder in French and Spanish studies (Perez, I et al. 1995;Leboyer et al. 1990)

Catecholamine synthesis (L-DOPA)

Phosphatidylinositol 4-phosphate, the product of PIK3C3 and phosphatidylinositol 4,5-bisphosphate, the product of PIP5K2A, stimulate TH activity in vitro (Morita et al. 1986).

 BDNF controls expression (Zhou et al. 1998). Expression controlled by TCF4 (Yoon and Chikaraishi 1994)

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

MAOA Monoamine oxidase A OMIM 309850 GeneCard

Xp11.3

Suggestive susceptibility locus in an NIMH pedigree (Zandi et al. 2003)

A number of studies have linked this gene to Bipolar disorder (Kirov et al. 1999)

Monoamine oxidase. The gene product oxidises dopamine, noradrenaline and serotonin, and other amines, generating H₂O₂ in the process (Youdim and Finberg 1991)

A number of studies have shown that the apoptotic effects of catecholamines can be related to the generation of H₂O₂ from MAO (Bianchi et al. 2003)

H₂O₂ decreases the expression of TrkB (BDNF receptor) at the cell surface (Olivieri et al. 2003). H₂O₂ oxidises BDNF  (Jensen et al. 2000). H₂O₂ derived from dopamine oxidises PLCG1 (Kim et al. 2002).

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

ADRBK2 adrenergic, beta, receptor kinase 2 GeneCard

22q12.1

OMIM MAFD1

A single nucleotide polymorphism of this gene has been associated with bipolar disorder (Barrett et al. 2003).

Beta adrenergic receptor kinase 2

Inhibited by PI 4,5 P2, product of PIP5K2A (Onorato et al. 1995)

Phosphorylates and inhibits DRD1 (Tiberi et al. 1996) and P2RX7 (Feng et al. 2005)

Decreased protein expression in lymphocyte cell lines isolated from bipolar patients (Niculescu, III et al. 2000). Stanley consortium Combined analysis: Downregulated (Higgs et al. 2006)

GNAZ guanine nucleotide binding protein (G protein), alpha z polypeptide GeneCard

22q11.2

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

GNAZ has been associated with bipolar disorder in an American study (Saito et al. 1999).

guanine nucleotide binding protein

Binds to PLCG1 (Bartlett and Hendry 1997)

DRD2, DRD3 receptors signal via GNAZ (Obadiah et al. 1999)

Reduced expression in olfactory neuroepithelial cells isolated from bipolar patients (McCurdy et al. 2006) .

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

ADCY9 Adenylate cyclase 9 GeneCard

16p13.3

Region linked to Bipolar disorder in a Genome-wide linkage scan (NIMH) (Cheng et al. 2006)

ADCY9 has been shown to be weakly associated with bipolar disorder in a family based study (Toyota et al. 2002).

This form of adenylate cyclase is coupled to GalphaS linked receptors including the beta-2 adrenoceptor (Small et al. 2003). It is inhibited by calcineurin (Paterson et al. 1995).

DRD2 receptor stimulation inhibits Galpha(s) stimulation of ADCY9 and Galpha(s) stimulation of ADCY9 is reduced by blocking ADCY9 glycosylation (Cumbay and Watts 2004). SSTR5 also signals via Galpha(s) and inhibits adenylate cyclase in in cho cells although the subtype of adenylate cyclase was not specifically identified (Carruthers et al. 1999)

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

SLC18A1 solute carrier family 18 (vesicular monoamine), member 1 GeneCard

8p21.3

Genes associated with bipolar disorder

Association studies

Primary role

Links to other Bipolar genes

Expression changes

HTR2A Serotonin receptor OMIM 182135 GeneCard

13q14-q21

13q14 described as a combined locus for both schizophrenia and Bipolar disorder in a Canadian study (Maziade et al. 2005). 13q21 also described in an american study (NIMH) (McInnis et al. 2003)

Three studies have reported association with Bipolar disorder (Ranade et al. 2003;Bonnier et al. 2002;Chee et al. 2001).

Serotonin

Stimulates  BDNF expression (Meller et al. 2002).  (Vaidya et al. 1997;Vaidya et al. 1999). Activates AKT1 in PC12 cells (Johnson-Farley et al. 2005) . Postsynaptic HTR2A receptors are markedly reduced in BDNF conditional knockout mice (Rios et al. 2006). Serotonin regulates GSK3B activity in the cortex, hippocampus and striatum in vivo and its phosphoylation at serine9 is increase by the combined administration of fenfluramine and clorgyline or by the serotonin uptake blockers fluoxetine or imipramine. 5HT1A receptors mediate increases and 5HT2 (HTR2A) receptors mediate decreases in GSK3B phosphorylation (Li et al. 2004). 

Reduced hippocampal mRNA expression (Lopez-Figueroa et al. 2004) (Knable et al. 2004).

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

HTR3A Serotonin receptor 3A GeneCard

11q23.1

One study has reported association of a polymorphism in HTR3A with bipolar disorder (Niesler et al. 2001).

Serotonin receptor/channel

Assembly and cell surface expression controlled by HSPA5 (Boyd et al. 2002). Serotonin receptor/channel:

HTR3 receptors activate  phospholipase D (Khan and Hichami 1999;Khan and Poisson 1999)whose product  Phosphatidic acid is a potent inhibitor of PI3 kinase (Lauener et al. 1995).

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

HTR3B Serotonin receptor 3B GeneCard

11q23.1

?

A 3 base pair deletion in the gene coding HTR3B is under-represented in a sample of Bipolar disorder patients (Frank et al. 2004a).

Serotonin receptor/channel

-

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

HTR4 Serotonin receptor 4 GeneCard

5q31-q33

5q33 linked to Bipolar disorder in a European study (Etain et al. 2006)

This receptor has been associated with Bipolar disorder in a Japanese study (Ohtsuki et al. 2002).

Activates adenylate cyclase (Dumuis et al. 1989). In hippocampal neurones, HTR4 activation increases neuronal excitability via a protein kinase A mediated inhibition of calcium-dependent potassium channels (Torres et al. 1995).

This receptor also activates the ERK kinases ERK1 (MAPK3) and ERK2 (MAPK1) via Ras and protein kinase A in HEK-293 cells (Norum et al. 2003). cAMP generated by 5HT-4 receptor activation also activates RAP1 via the guanine nucleotide-exchange factor Epac1 (RAPGEF3) and this leads to activation of the small GTPase Rac (Maillet et al. 2003). RAPGEF3 is able to activate PI3 kinases in other models (Sable et al. 1997;Filippa et al. 1999;Mei et al. 2002) but the effects of HTR4 receptor stimulation have not been specifically examined.

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

HTR5A
 Serotonin receptor OMIM 601305 GeneCard

7q36.1

7q36 linked to Bipolar disorder in a European study (Etain et al. 2006)

A polymorphism associating with bipolar disorder has been reported in one study (Birkett et al. 2000).

Localised in the suprachiasmatic nucleus. Activation can produce phase shifts of the circadian clock (Sprouse et al. 2004)Negatively coupled to adenylate cyclase (Nelson 2004). In C6 glioma cells HTR5A activation increases the accumulation of inositol 1,4,5 triphosphate and inhibit ADP ribosyl cyclase activity via G-protein linked pathways (Noda et al. 2003).Cyclic ADP ribose, the product of this enzyme increases ryanodine-sensitive intracellular calcium mobilisation (Meszaros et al. 1993). (see Circadian genes)

Cyclic ADPribose activates TRPM2 (Togashi et al. 2006)

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

HTR6Serotonin receptor OMIM 601109 GeneCard

1p36-p35

1p35-36 identified as a susceptibility locus in a European study (Schumacher et al. 2005)

A limited association between bipolar disorder and this receptor has been observed in one study (Vogt et al. 2000).

Positively coupled to adenylate cyclase (Grimaldi et al. 1998).

-

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

SLC6A4 Serotonin transporter OMIM 182138 GeneCard

17q11.1-q12

Region linked to bipolar disorder (see review of genome scans (Levinson 2005)

Numerous  studies support association of this transporter to unipolar, bipolar and seasonal affective disorders (Lotrich and Pollock 2004)

Serotonin transporter

BDNF increases expression in embryonic rat raphe (Rumajogee et al. 2002). Synaptosomal serotonin transport is inhibited by tetanus toxin an effect mediated by tyrosine kinase receptor activation and a subsequent increase in PLCG1 phosphorylation (Najib et al. 2000).

Increased frontal cortex mRNA expression (Sun et al. 2001). Reduced affinity for [3H]citalopram in molecular layer of the hippocampus (Dean et al. 2003). Reduced imipramine binding in platelets of unaffected relatives of bipolar patients (Kd and Bmax) (Leboyer et al. 1999)

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

Genes associated with bipolar disorder

Association studies

Primary role

Links to other Bipolar genes

Expression changes

GABRA1 gamma-aminobutyric acid (GABA) A receptor, alpha 1 GeneCard

5q34-q35

(Horiuchi et al. 2004)

GABA receptor

PDGF receptors inactivate GABA receptors (Valenzuela et al. 1995) in rat hippocampal neurones and independently of their subunit composition via activation of PLCG1. In contrast, BDNF promotes the cell surface clustering of GABAA receptors via activation of PLCG1 and subsequent increases in intracellular calcium (Mizoguchi et al. 2003).

No change in immunocytochemical study in prefrontal cortex (Ishikawa et al. 2004)

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

GABRA5 gamma-aminobutyric acid (GABA) A receptor, alpha 5 GeneCard

15q11.2-q12

15q11 decribed a s a susceptibility locvus in a Canadian study(Maziade et al. 2005)

(De bruyn et al. 1996;Otani et al. 2005;Papadimitriou et al. 1998) U K WTCCC study Craddock et al, 2010

GABA

In developing neurones the chloride gradient is such as to enable GABA (GABRA1, GABRA5) to promote excitation rather than inhibition. GABA-related depolarisation can activate calcium channels and activate downstream signaling cascades.  In the developing hypothalamus GABA and muscimol activate the MAPK/CREB pathway and increase the expression of BDNF (Obrietan et al. 2002). Similar effects have been observed in hippocampal culture where the effects of GABA switch from increasing to decreasing BDNF expression during maturation, in parallel with the switch of GABA actions from excitation to inhibition (Marty et al. 1996;Berninger et al. 1995) The excitatory effects of GABA also contribute to the trophic effects of this transmitter in developing oligodendrocytes (Wang et al. 2003). In the adult brain, where GABA is inhibitory, GABA-A receptor activation reduces BDNF and NGF expression in the hippocampus (Zafra et al. 1991).

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

GAD1 Glutamate decarboxylase 1 OMIM  605363 GeneCard 2q31

Suggested susceptibility locus in german and danish studies (Cichon et al. 2001;Ewald et al. 2003)

Weak association reported in a Danish study (Lundorf et al. 2005)

GABA synthesis

Transcription controlled by BDNF in rat striatal neurones (Mizuno et al. 1994)

Reduced hippocampal protein (Knable et al. 2004), Decreased number of GAD67-positive neurones in Brodmann area 9 (Veldic et al. 2005) and in cerebellum (Fatemi et al. 2005). Reduced density of GRIN2A receptor bearing GAD67-positive neurones in layer 2 of cingulate cortex (Woo et al. 2004). Reduced mRNA expression in prefrontal cortex (Guidotti et al. 2000).Reduced mRNA density in CA4 hippocampal region (Heckers et al. 2002).