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Association between the PPP3CC gene, coding for the calcineurin gamma catalytic subunit, and bipolar disorder

Association between the PPP3CC gene, coding for the calcineurin gamma catalytic subunit, and... Background: Calcineurin is a neuron-enriched phosphatase that regulates synaptic plasticity and neuronal adaptation. Activation of calcineurin, overall, antagonizes the effects of the cyclic AMP activated protein/kinase A. Thus, kinase/phosphatase dynamic balance seems to be critical for transition to long- term cellular responses in neurons, and disruption of this equilibrium should induce behavioral impairments in animal models. Genetic animal models, as well as post-mortem studies in humans have implicated calcineurin dependent calcium and cyclic AMP regulated phosphorylation/dephosphorylation in both affective responses and psychosis. Recently, genetic association between schizophrenia and genetic variation of the human calcineurin A gamma subunit gene (PPP3CC) has been reported. Methods: Based on the assumption of the common underlying genetic factor in schizophrenia and bipolar affective disorder (BPAD), we performed association analysis of CC33 and CCS3 polymorphisms of the PPP3CC gene reported to be associated with schizophrenia in a French sample of 115 BPAD patients and 97 healthy controls. Results: Carrying 'CT' or 'TT' genotypes of the PPP3CC-CC33 polymorphism increased risk to develop BPAD comparing to carry 'CC' genotype (OR = 1.8 [1.01–3.0]; p = 0.05). For the PPP3CC-CCS3 polymorphism, 'AG' or 'GG' carriers have an increased risk to develop BPAD than 'AA' carriers (OR = 2.8 [1.5–5.2]). The CC33 and CCS3 polymorphisms were observed in significant linkage disequilibrium (D' = 0.91, r = 0.72). Haplotype frequencies were significantly different in BPAD patients than in controls (p = 0.03), with a significant over-transmission of the 'TG' haplotype in BPAD patients (p = 0.001). Conclusion: We suggest that the PPP3CC gene might be a susceptibility gene for BPAD, in accordance with current neurobiological hypotheses that implicate dysregulation of signal-transduction pathways, such as those regulated by calcineurin, in the etiology of affective disorders. Page 1 of 4 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:2 http://www.behavioralandbrainfunctions.com/content/4/1/2 Background Methods Calcineurin (CN; also known as Ca2+/protein phos- We hypothesized that variants in the PPP3CC catalytic phatase 2B) is a neuron enriched calcium/calmodulin subunit might also predispose to BPAD. We investigated stimulated serine/threonine phosphatase composed of a the association between PPP3CC and bipolar-affective- regulatory subunit (CNB) and a catalytic subunit (CNA). disorder (BPAD) in a Caucasian French population of 115 There are three mammalian calcineurin catalytic isoforms BPAD patients and 97 healthy controls. BPAD patients (CNA α, β and γ) and two regulatory isoforms (CNB1 and were recruited at two French University-affiliated Psychi- CNB2). Acting as calcium-sensor, calcium-G protein sign- atric Departments (one in Paris and one in Bordeaux). aling integrator, and regulator of calcium homeostasis, Inclusion criteria comprised: BPAD I or II diagnosis calcineurin shapes calcium and cyclic AMP dependent (according to DSM-IV criteria); Caucasian origin with at processes: synaptic activity, receptor desensitization, cell least three out of four grandparents being French; being at survival, neuroplasticity, cellular resilience [1]. Cal- least 18 years old; being euthymic (having a MADRS cineurin activation, overall, opposes cyclic AMP/PKA (Montgomery-Asberg Depressive Rating Scale) score of fif- actions, and the fine-tuning of this kinase/phosphatase teen or less and a MAS (Bech and Raphaelsen Mania Rat- balance is critical for neuronal adaptation, transition to ing Scale) score of five or less) at inclusion. The control long-term responses and higher functions including sen- group comprised randomly selected blood donors having sitivity to aversive stimuli, fear conditioning, and impor- no personal or family history of any psychiatric disorder. tantly learning and memory [1]. Written informed consent was obtained from all partici- pants. A trained psychiatrist using the French version of Recently, different lines of evidence have suggested that the Diagnostic Interview for Genetic Studies (DIGS) pro- calcineurin could be a possible risk factor of schizophre- viding lifetime DSM-IV axis I diagnoses interviewed nia. Most importantly, Gerber and collaborators [2] patients and control subjects. Male/female ratio was 0.72 reported the association of schizophrenia with genetic in BPAD patients and 1.68 in controls. Based on the variation of the PPP3CC gene, which encodes the CNA-γ- PPP3CC/schizophrenia association study [2], we geno- subunit in a Caucasian population. The PPP3CC catalytic typed the two intronic single-nucleotide polymorphisms subunit of calcineurin is located at 8p21, a highly repli- (SNPs) showing strongest evidence for linkage (CC33T/C cated schizophrenia susceptibility locus, and variants and CCS3A/G). We also genotyped the coding sequence within the gene are associated with schizophrenia. This mutation identified [2] on PPP3CC exon 5, resulting in a association is not seen in a Japanese sample [3]. However, nonconservative change in the amino acid sequence of the studies with transgenic animal models [4,5] show that protein from a charged arginine at position 163 to a neu- forebrain specific CNB knockout mice display behavioral tral glutamine (CC-5). abnormalities reminiscent of both schizophrenia, such as increased locomotion, decreased social interaction and Results and discussion deficits in working memory and sensorimotor gating. In We identified the CC-5 mutation in 3 patients and in 0 addition pharmacological [6,7] studies in animals, as well controls, a frequency comparable to that of the PPP3CC/ as post-mortem findings in schizophrenic patients [[8] schizophrenia study (i.e. 3 of 210 tested patients and 0 of but see [9]] show that expression of calcineurin is altered 75 Caucasian controls; [2]). For CC33 and CCS3, Hardy- upon treatment with anti-psychotics and expression of the Weinberg-equilibrium was tested separately in cases and PPP3CC and other calcineurin subunits is decreased in controls. We also estimated linkage disequilibrium values the hippocampus of schizophrenic patients further impli- D' and r [14,15]. We tested for disease-haplotype associ- cating calcineurin in neuropsychiatric disorders, such as ation by likelihood-based approaches using the EH-plus schizophrenia [10]. software [16]. No deviation from Hardy-Weinberg-equi- librium was observed for CC33 and CCS3, in both groups. Alterations in calcineurin signaling may also be involved Association between BPAD and CC33 genotype was bor- in bipolar affective disorder (BPAD). Many of the pheno- derline significant (p = 0.07), with an higher risk to types of the CNB knock out mouse are also relevant to develop bipolar disorder for 'CT' or 'TT' carriers versus BPAD, calcineurin subunits are down-regulated in the pre- 'CC' carriers (OR = 1.8 [1.01–3.0]; p = 0.05) and a signif- frontal cortex of BPAD patients and other genes involved icant allelic association was observed with the 'T'-allele of in calcineurin signaling, DARPP-32 (dopamine and cyclic CC33 (p = 0.05, see Table 1 for details). Our results show AMP regulated phosphoprotein of Mr 32,000), CDK5 also a significant association between BPAD and CCS3 (p (cyclin dependent kinase5), GSK3 (glycogen kinase syt- = 0.003), with an higher risk to develop bipolar disorder nthase 3) and the calcineurin activated adenylyl cyclase 9, for 'AG' or 'GG' carriers versus 'AA' carriers (OR = 2.8 [1.5– have been associated with BPAD [11,12]. Finally, 8p21 5.2]) and a significant allelic association between the 'G'- has also been identified as a highly significant susceptibil- allele of CCS3 and BPAD was observed (p = 0.002, see ity locus for a psychotic form of BPAD [13]. table 1 for details). The CC33 and CCS3 polymorphisms Page 2 of 4 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:2 http://www.behavioralandbrainfunctions.com/content/4/1/2 Table 1: Genotypic, Allelic and Haplotype association study of PPP3CC -CC33 and -CCS3 polymorphisms Allele Count Cases Controls OR [CI_95%] p-value CC33 CC 39 46 (CT+TT) versus CC 1.8 [1.01–3.0] 0.05 CT 52 36 TT 24 15 f(C) 0.57 0.66 - f(T) 0.43 0.34 1.5 [1.01–2.2] 0.05 CCS3 Allele frequencies Cases Controls OR [CI_95%] p-value AA 22 39 (GG+AG) vs AA 2.8 [1.5–5.2] 0.001 AG 60 41 GG 27 14 f(A) 0.48 0.63 - f(G) 0.52 0.37 1.9 [1.3–2.8] 0.002 CC33/CCS3 Haplotype frequencies Cases Controls Chi-Square p-value CA 0.47 0.61 TG versus (C2+CG+TA) 16.2 0.001 CG 0.09 0.05 TA - 0.02 TG 0.44 0.32 were observed in significant linkage disequilibrium (D' = females OR = 2.57 [1.57–4.21]). However, association 0.91, r = 0.72). Haplotype frequencies were significantly between bipolar disorder and CC33 is significant only for different in BPAD patients than in controls (Likelihood females (p < 0.001). Also association of CC33 haplotypes 2 2 ratio test: Chi (3 ddf) = 9.08, p = 0.03), and a significant was significant in females (Chi (3 df) = 50.6; p < 0.001) over-transmission of the PPP3CC haplotype 'TG' (p = and not significant in males (Chi (3 df) = 4.4; p = 0.22). 0.001) was observed for bipolar patients. HapMap LD An over transmission of 'TG' haplotype was observed for data for the PPP3CC gene support the association being bipolar males and female patients. due to a variant in PPP3CC and not a nearby gene. Our results suggest that the PPP3CC gene may contribute In order to test an association between psychotic symp- to the etiology of BPAD. This is in accordance with pre- toms and PPP3CC polymorphisms, we have compared clinical work that relates calcineurin related signaling genotypic repartition in psychotic (N = 59) versus non- pathways to the pathophysiology of affective and cogni- psychotic (N = 56) patients for both CC33 and CCS3 pol- tive disorders. Specifically it was shown that phosphatase ymorphism. No difference was observed. Moreover, psy- activity/amount could predict whether a signaling system chotic and non-psychotic patient samples shown similar will operate in a proportional-response-mode, or as an association when compared to controls, suggesting that all-or-none-switch [17] susceptible to generate dispropor- these variants are implicated in bipolar disorder per se tional network responses. This might be relevant to the and are not specific of psychotic symptoms. bidirectional behavioral dysfunction (depressed or agi- tated mood) characterizing BPAD. Furthermore, as stated As male/female ratio was significantly different between above, preclinical studies have implicated calcineurin in patients and controls, we have performed genotypic and cognitive function as well as in affective responsiveness haplotypic analyses stratified on gender. Similar results [1,5,18]. Our present findings suggest that PPP3CC might were observed: a higher risk to develop bipolar disorder be a shared susceptibility gene for schizophrenia and for 'CT' or 'TT' carriers for CC33: OR = 1.45 [0.67–3.15] BPAD. Calcineurin dysregulation, therefore, might be for males and females OR = 2.54 [1.10–5.91]; association associated with transnosographic phenotypical aspects, between bipolar disorder and CC33 being significant only such as affective and cognitive pathology, seen in both for females (p = 0.03). For CCS3 polymorphism, 'AG' or disorders. 'GG' carriers have a higher risk than 'AA' carriers to develop disease, (males OR = 1.29 [0.92–1.83] and Page 3 of 4 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:2 http://www.behavioralandbrainfunctions.com/content/4/1/2 4. Miyakawa T, Leiter LM, Gerber DJ, Gainetdinov RR, Sotnikova TD, Conclusion Zeng H, Caron MG, Tonegawa S: Conditional calcineurin knock- We suggest that the PPP3CC gene might be a susceptibility out mice exhibit multiple abnormal behaviors related to gene for BPAD, in accordance with the current neurobio- schizophrenia. Proc Natl Acad Sci U S A 2003, 100:8987-8992. 5. Zeng H, Chattarji S, Barbarosie M, Rondi-Reig L, Philpot BD, Miya- logical hypothesis that implicates dysregulation of signal- kawa T, Bear FM, Tonegawa S: Forebrain-specific calcineurin transduction pathways, such as those regulated by cal- knockout selectively impairs bidirectional synaptic plasticity and working/episodic-like memory. Cell 2001, 107:617-629. cineurin, in the etiology of affective disorders. We would 6. Kontkanen O, Toronen P, Lakso M, Wong G, Castren E: Antipsy- like however to point out some limitations related to our chotic drug treatment induces differential gene expression approach. One must be aware that case/control associa- in the rat cortex. J Neurochem 2002, 83:1043-1053. 7. Rushlow WJ, Seah YH, Belliveau DJ, Rajakumar N: Changes in cal- tion studies often lead to non-replicable results. In this cineurin expression induced in the rat brain by the adminis- respect our population is very small and ethnographic tration of antipsychotics. J Neurochem 2005, 94:587-596. bias cannot be excluded. In conclusion this is a case/con- 8. Eastwood SL, Burnet PW, Harrison PJ: Decreased hippocampal expression of the susceptibility gene PPP3CC and other cal- trol report with limited power that reports for the first cineurin subunits in schizophrenia. Biol Psychiatry 2005, time an association between calcineurin and BPAD. Fur- 57:702-710. 9. Kozlovsky N, Scarr E, Dean B, Agam G: Postmortem brain cal- ther investigations with larger samples are warranted to cineurin protein levels in schizophrenia patients are not dif- confirm this result. ferent from controls. Schizophr Res 2006, 83:173-177. 10. Manji HK, Gottesman II, Gould TD: Signal transduction and genes-to-behaviors pathways in psychiatric diseases. Sci STKE Abbreviations 2003, 207:e49. BPAD: Bipolar affective disorder; CN: Calcineurin. 11. Toyota T, Yamada K, Saito K, Detera-Wadleigh SD, Yoshikawa T: Association analysis of adenylate cyclase type 9 gene using pedigree disequilibrium test in bipolar disorder. Mol Psychiatry Competing interests 2002, 7:450-452. The author(s) declare that they have no competing inter- 12. Ogden CA, Rich ME, Schork NJ, Paulus MP, Geyer MA, Lohr JB, Kuc- zenski R, Niculescu AB: Candidate genes, pathways and mech- ests. anisms for bipolar (manic-depressive) and related disorders: an expanded convergent functional genomics approach. Mol Authors' contributions Psychiatry 2004, 9:1007-1029. 13. Park N, Juo SH, Cheng R, Liu J, Loth JE, Lilliston B, Nee J, Grunn A, FM and SM contributed equally to this work. FM partici- Kanyas K, Lerer B, Endicott J, Gilliam TC, Baron M: Linkage analysis pated in the study design and coordination, performed of psychosis in bipolar pedigrees suggests novel putative loci for bipolar disorder and shared susceptibility with schizo- statistical analysis and wrote the manuscript, SM carried phrenia. Mol Psychiatry 2004, 9:1091-1099. out the molecular genetic studies, participated in the 14. Lewontin RC, Feldman MW: A general asymptotic property of sequence alignment, collacted and analyzed the data and two-locus selection models. Theor Popul Biol 1988, 34:177-193. 15. Wall JD, Pritchard JK: Haplotype blocks and linkage disequilib- drafted the manuscript, BE and FB paricipated in patient rium in the human genome. Nat Rev Genet 2003, 4:587-597. recruitment, interview and evaluation, M-A. EK and FC 16. Terwilliger J, Ott J: Handbook of Human Genetic Linkage Balti- participated in the genotyping, ML is the principal inves- more:Johns Hopkins University Press; 1994. 17. Bhalla US, Ram PT, Iyengar R: MAP kinase phosphatase as a locus tigator of the clinical protocols, BG is the principal inves- of flexibility in a mitogen-activated protein kinase signaling tigator of the molecular protocols, ETT participated in network. Science 2002, 297:1018-1023. 18. Crozatier C, Farley S, Mansuy IM, Dumas S, Giros B, Tzavara ET: Cal- study design and coordination, participated in patient cineurin (protein phosphatase 2B) is involved in the mecha- interview and genotyping, collected data and wrote the nisms of action of antidepressants. Neuroscience 2007, manuscript. 144:1470-1476. Acknowledgements This work was supported by Insitut national de la Sante et de la Recherche Medicale (INSERM), Assistance Publique – Hopitaux de Paris (AP-HP), AP- HP/INSERM contrat d'interface (to E.T.T), Agence National pour la Recher- che (ANR-Project ManageBP), Fondation pour la Recherche sur le Cer- veau, and National Alliance for Research on Schizophrenia and Depression. Written informed consent was obtained for research and publication from Publish with Bio Med Central and every the patients and/or their relatives. scientist can read your work free of charge "BioMed Central will be the most significant development for References disseminating the results of biomedical researc h in our lifetime." 1. Xia Z, Storm DR: The role of calmodulin as a signal integrator Sir Paul Nurse, Cancer Research UK for synaptic plasticity. Nat Rev Neurosci 2005, 6:267-276. 2. Gerber DJ, Hall D, Miyakawa T, Demars S, Gogos JA, Karayiorgou M, Your research papers will be: Tonegawa S: Evidence for association of schizophrenia with available free of charge to the entire biomedical community genetic variation in the 8p21.3 gene, PPP3CC, encoding the calcineurin gamma subunit. Proc Natl Acad Sci U S A 2003, peer reviewed and published immediately upon acceptance 100:8993-8998. cited in PubMed and archived on PubMed Central 3. Kinoshita Y, Suzuki T, Ikeda M, Kitajima T, Yamanouchi Y, Inada T, Yoneda H, Iwata N, Ozaki N: No association with the calcineurin yours — you keep the copyright A gamma subunit gene (PPP3CC) haplotype to Japanese BioMedcentral Submit your manuscript here: schizophrenia. J Neural Transm 2005, 112:1255-1262. http://www.biomedcentral.com/info/publishing_adv.asp Page 4 of 4 (page number not for citation purposes) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Behavioral and Brain Functions Springer Journals

Association between the PPP3CC gene, coding for the calcineurin gamma catalytic subunit, and bipolar disorder

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Springer Journals
Copyright
Copyright © 2008 by Mathieu et al; licensee BioMed Central Ltd.
Subject
Biomedicine; Neurosciences; Neurology; Behavioral Therapy; Psychiatry
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1744-9081
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10.1186/1744-9081-4-2
pmid
18201382
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Abstract

Background: Calcineurin is a neuron-enriched phosphatase that regulates synaptic plasticity and neuronal adaptation. Activation of calcineurin, overall, antagonizes the effects of the cyclic AMP activated protein/kinase A. Thus, kinase/phosphatase dynamic balance seems to be critical for transition to long- term cellular responses in neurons, and disruption of this equilibrium should induce behavioral impairments in animal models. Genetic animal models, as well as post-mortem studies in humans have implicated calcineurin dependent calcium and cyclic AMP regulated phosphorylation/dephosphorylation in both affective responses and psychosis. Recently, genetic association between schizophrenia and genetic variation of the human calcineurin A gamma subunit gene (PPP3CC) has been reported. Methods: Based on the assumption of the common underlying genetic factor in schizophrenia and bipolar affective disorder (BPAD), we performed association analysis of CC33 and CCS3 polymorphisms of the PPP3CC gene reported to be associated with schizophrenia in a French sample of 115 BPAD patients and 97 healthy controls. Results: Carrying 'CT' or 'TT' genotypes of the PPP3CC-CC33 polymorphism increased risk to develop BPAD comparing to carry 'CC' genotype (OR = 1.8 [1.01–3.0]; p = 0.05). For the PPP3CC-CCS3 polymorphism, 'AG' or 'GG' carriers have an increased risk to develop BPAD than 'AA' carriers (OR = 2.8 [1.5–5.2]). The CC33 and CCS3 polymorphisms were observed in significant linkage disequilibrium (D' = 0.91, r = 0.72). Haplotype frequencies were significantly different in BPAD patients than in controls (p = 0.03), with a significant over-transmission of the 'TG' haplotype in BPAD patients (p = 0.001). Conclusion: We suggest that the PPP3CC gene might be a susceptibility gene for BPAD, in accordance with current neurobiological hypotheses that implicate dysregulation of signal-transduction pathways, such as those regulated by calcineurin, in the etiology of affective disorders. Page 1 of 4 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:2 http://www.behavioralandbrainfunctions.com/content/4/1/2 Background Methods Calcineurin (CN; also known as Ca2+/protein phos- We hypothesized that variants in the PPP3CC catalytic phatase 2B) is a neuron enriched calcium/calmodulin subunit might also predispose to BPAD. We investigated stimulated serine/threonine phosphatase composed of a the association between PPP3CC and bipolar-affective- regulatory subunit (CNB) and a catalytic subunit (CNA). disorder (BPAD) in a Caucasian French population of 115 There are three mammalian calcineurin catalytic isoforms BPAD patients and 97 healthy controls. BPAD patients (CNA α, β and γ) and two regulatory isoforms (CNB1 and were recruited at two French University-affiliated Psychi- CNB2). Acting as calcium-sensor, calcium-G protein sign- atric Departments (one in Paris and one in Bordeaux). aling integrator, and regulator of calcium homeostasis, Inclusion criteria comprised: BPAD I or II diagnosis calcineurin shapes calcium and cyclic AMP dependent (according to DSM-IV criteria); Caucasian origin with at processes: synaptic activity, receptor desensitization, cell least three out of four grandparents being French; being at survival, neuroplasticity, cellular resilience [1]. Cal- least 18 years old; being euthymic (having a MADRS cineurin activation, overall, opposes cyclic AMP/PKA (Montgomery-Asberg Depressive Rating Scale) score of fif- actions, and the fine-tuning of this kinase/phosphatase teen or less and a MAS (Bech and Raphaelsen Mania Rat- balance is critical for neuronal adaptation, transition to ing Scale) score of five or less) at inclusion. The control long-term responses and higher functions including sen- group comprised randomly selected blood donors having sitivity to aversive stimuli, fear conditioning, and impor- no personal or family history of any psychiatric disorder. tantly learning and memory [1]. Written informed consent was obtained from all partici- pants. A trained psychiatrist using the French version of Recently, different lines of evidence have suggested that the Diagnostic Interview for Genetic Studies (DIGS) pro- calcineurin could be a possible risk factor of schizophre- viding lifetime DSM-IV axis I diagnoses interviewed nia. Most importantly, Gerber and collaborators [2] patients and control subjects. Male/female ratio was 0.72 reported the association of schizophrenia with genetic in BPAD patients and 1.68 in controls. Based on the variation of the PPP3CC gene, which encodes the CNA-γ- PPP3CC/schizophrenia association study [2], we geno- subunit in a Caucasian population. The PPP3CC catalytic typed the two intronic single-nucleotide polymorphisms subunit of calcineurin is located at 8p21, a highly repli- (SNPs) showing strongest evidence for linkage (CC33T/C cated schizophrenia susceptibility locus, and variants and CCS3A/G). We also genotyped the coding sequence within the gene are associated with schizophrenia. This mutation identified [2] on PPP3CC exon 5, resulting in a association is not seen in a Japanese sample [3]. However, nonconservative change in the amino acid sequence of the studies with transgenic animal models [4,5] show that protein from a charged arginine at position 163 to a neu- forebrain specific CNB knockout mice display behavioral tral glutamine (CC-5). abnormalities reminiscent of both schizophrenia, such as increased locomotion, decreased social interaction and Results and discussion deficits in working memory and sensorimotor gating. In We identified the CC-5 mutation in 3 patients and in 0 addition pharmacological [6,7] studies in animals, as well controls, a frequency comparable to that of the PPP3CC/ as post-mortem findings in schizophrenic patients [[8] schizophrenia study (i.e. 3 of 210 tested patients and 0 of but see [9]] show that expression of calcineurin is altered 75 Caucasian controls; [2]). For CC33 and CCS3, Hardy- upon treatment with anti-psychotics and expression of the Weinberg-equilibrium was tested separately in cases and PPP3CC and other calcineurin subunits is decreased in controls. We also estimated linkage disequilibrium values the hippocampus of schizophrenic patients further impli- D' and r [14,15]. We tested for disease-haplotype associ- cating calcineurin in neuropsychiatric disorders, such as ation by likelihood-based approaches using the EH-plus schizophrenia [10]. software [16]. No deviation from Hardy-Weinberg-equi- librium was observed for CC33 and CCS3, in both groups. Alterations in calcineurin signaling may also be involved Association between BPAD and CC33 genotype was bor- in bipolar affective disorder (BPAD). Many of the pheno- derline significant (p = 0.07), with an higher risk to types of the CNB knock out mouse are also relevant to develop bipolar disorder for 'CT' or 'TT' carriers versus BPAD, calcineurin subunits are down-regulated in the pre- 'CC' carriers (OR = 1.8 [1.01–3.0]; p = 0.05) and a signif- frontal cortex of BPAD patients and other genes involved icant allelic association was observed with the 'T'-allele of in calcineurin signaling, DARPP-32 (dopamine and cyclic CC33 (p = 0.05, see Table 1 for details). Our results show AMP regulated phosphoprotein of Mr 32,000), CDK5 also a significant association between BPAD and CCS3 (p (cyclin dependent kinase5), GSK3 (glycogen kinase syt- = 0.003), with an higher risk to develop bipolar disorder nthase 3) and the calcineurin activated adenylyl cyclase 9, for 'AG' or 'GG' carriers versus 'AA' carriers (OR = 2.8 [1.5– have been associated with BPAD [11,12]. Finally, 8p21 5.2]) and a significant allelic association between the 'G'- has also been identified as a highly significant susceptibil- allele of CCS3 and BPAD was observed (p = 0.002, see ity locus for a psychotic form of BPAD [13]. table 1 for details). The CC33 and CCS3 polymorphisms Page 2 of 4 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:2 http://www.behavioralandbrainfunctions.com/content/4/1/2 Table 1: Genotypic, Allelic and Haplotype association study of PPP3CC -CC33 and -CCS3 polymorphisms Allele Count Cases Controls OR [CI_95%] p-value CC33 CC 39 46 (CT+TT) versus CC 1.8 [1.01–3.0] 0.05 CT 52 36 TT 24 15 f(C) 0.57 0.66 - f(T) 0.43 0.34 1.5 [1.01–2.2] 0.05 CCS3 Allele frequencies Cases Controls OR [CI_95%] p-value AA 22 39 (GG+AG) vs AA 2.8 [1.5–5.2] 0.001 AG 60 41 GG 27 14 f(A) 0.48 0.63 - f(G) 0.52 0.37 1.9 [1.3–2.8] 0.002 CC33/CCS3 Haplotype frequencies Cases Controls Chi-Square p-value CA 0.47 0.61 TG versus (C2+CG+TA) 16.2 0.001 CG 0.09 0.05 TA - 0.02 TG 0.44 0.32 were observed in significant linkage disequilibrium (D' = females OR = 2.57 [1.57–4.21]). However, association 0.91, r = 0.72). Haplotype frequencies were significantly between bipolar disorder and CC33 is significant only for different in BPAD patients than in controls (Likelihood females (p < 0.001). Also association of CC33 haplotypes 2 2 ratio test: Chi (3 ddf) = 9.08, p = 0.03), and a significant was significant in females (Chi (3 df) = 50.6; p < 0.001) over-transmission of the PPP3CC haplotype 'TG' (p = and not significant in males (Chi (3 df) = 4.4; p = 0.22). 0.001) was observed for bipolar patients. HapMap LD An over transmission of 'TG' haplotype was observed for data for the PPP3CC gene support the association being bipolar males and female patients. due to a variant in PPP3CC and not a nearby gene. Our results suggest that the PPP3CC gene may contribute In order to test an association between psychotic symp- to the etiology of BPAD. This is in accordance with pre- toms and PPP3CC polymorphisms, we have compared clinical work that relates calcineurin related signaling genotypic repartition in psychotic (N = 59) versus non- pathways to the pathophysiology of affective and cogni- psychotic (N = 56) patients for both CC33 and CCS3 pol- tive disorders. Specifically it was shown that phosphatase ymorphism. No difference was observed. Moreover, psy- activity/amount could predict whether a signaling system chotic and non-psychotic patient samples shown similar will operate in a proportional-response-mode, or as an association when compared to controls, suggesting that all-or-none-switch [17] susceptible to generate dispropor- these variants are implicated in bipolar disorder per se tional network responses. This might be relevant to the and are not specific of psychotic symptoms. bidirectional behavioral dysfunction (depressed or agi- tated mood) characterizing BPAD. Furthermore, as stated As male/female ratio was significantly different between above, preclinical studies have implicated calcineurin in patients and controls, we have performed genotypic and cognitive function as well as in affective responsiveness haplotypic analyses stratified on gender. Similar results [1,5,18]. Our present findings suggest that PPP3CC might were observed: a higher risk to develop bipolar disorder be a shared susceptibility gene for schizophrenia and for 'CT' or 'TT' carriers for CC33: OR = 1.45 [0.67–3.15] BPAD. Calcineurin dysregulation, therefore, might be for males and females OR = 2.54 [1.10–5.91]; association associated with transnosographic phenotypical aspects, between bipolar disorder and CC33 being significant only such as affective and cognitive pathology, seen in both for females (p = 0.03). For CCS3 polymorphism, 'AG' or disorders. 'GG' carriers have a higher risk than 'AA' carriers to develop disease, (males OR = 1.29 [0.92–1.83] and Page 3 of 4 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:2 http://www.behavioralandbrainfunctions.com/content/4/1/2 4. Miyakawa T, Leiter LM, Gerber DJ, Gainetdinov RR, Sotnikova TD, Conclusion Zeng H, Caron MG, Tonegawa S: Conditional calcineurin knock- We suggest that the PPP3CC gene might be a susceptibility out mice exhibit multiple abnormal behaviors related to gene for BPAD, in accordance with the current neurobio- schizophrenia. Proc Natl Acad Sci U S A 2003, 100:8987-8992. 5. Zeng H, Chattarji S, Barbarosie M, Rondi-Reig L, Philpot BD, Miya- logical hypothesis that implicates dysregulation of signal- kawa T, Bear FM, Tonegawa S: Forebrain-specific calcineurin transduction pathways, such as those regulated by cal- knockout selectively impairs bidirectional synaptic plasticity and working/episodic-like memory. Cell 2001, 107:617-629. cineurin, in the etiology of affective disorders. We would 6. Kontkanen O, Toronen P, Lakso M, Wong G, Castren E: Antipsy- like however to point out some limitations related to our chotic drug treatment induces differential gene expression approach. One must be aware that case/control associa- in the rat cortex. J Neurochem 2002, 83:1043-1053. 7. Rushlow WJ, Seah YH, Belliveau DJ, Rajakumar N: Changes in cal- tion studies often lead to non-replicable results. In this cineurin expression induced in the rat brain by the adminis- respect our population is very small and ethnographic tration of antipsychotics. J Neurochem 2005, 94:587-596. bias cannot be excluded. In conclusion this is a case/con- 8. Eastwood SL, Burnet PW, Harrison PJ: Decreased hippocampal expression of the susceptibility gene PPP3CC and other cal- trol report with limited power that reports for the first cineurin subunits in schizophrenia. Biol Psychiatry 2005, time an association between calcineurin and BPAD. Fur- 57:702-710. 9. Kozlovsky N, Scarr E, Dean B, Agam G: Postmortem brain cal- ther investigations with larger samples are warranted to cineurin protein levels in schizophrenia patients are not dif- confirm this result. ferent from controls. Schizophr Res 2006, 83:173-177. 10. Manji HK, Gottesman II, Gould TD: Signal transduction and genes-to-behaviors pathways in psychiatric diseases. Sci STKE Abbreviations 2003, 207:e49. BPAD: Bipolar affective disorder; CN: Calcineurin. 11. Toyota T, Yamada K, Saito K, Detera-Wadleigh SD, Yoshikawa T: Association analysis of adenylate cyclase type 9 gene using pedigree disequilibrium test in bipolar disorder. Mol Psychiatry Competing interests 2002, 7:450-452. The author(s) declare that they have no competing inter- 12. Ogden CA, Rich ME, Schork NJ, Paulus MP, Geyer MA, Lohr JB, Kuc- zenski R, Niculescu AB: Candidate genes, pathways and mech- ests. anisms for bipolar (manic-depressive) and related disorders: an expanded convergent functional genomics approach. Mol Authors' contributions Psychiatry 2004, 9:1007-1029. 13. Park N, Juo SH, Cheng R, Liu J, Loth JE, Lilliston B, Nee J, Grunn A, FM and SM contributed equally to this work. FM partici- Kanyas K, Lerer B, Endicott J, Gilliam TC, Baron M: Linkage analysis pated in the study design and coordination, performed of psychosis in bipolar pedigrees suggests novel putative loci for bipolar disorder and shared susceptibility with schizo- statistical analysis and wrote the manuscript, SM carried phrenia. Mol Psychiatry 2004, 9:1091-1099. out the molecular genetic studies, participated in the 14. Lewontin RC, Feldman MW: A general asymptotic property of sequence alignment, collacted and analyzed the data and two-locus selection models. Theor Popul Biol 1988, 34:177-193. 15. Wall JD, Pritchard JK: Haplotype blocks and linkage disequilib- drafted the manuscript, BE and FB paricipated in patient rium in the human genome. Nat Rev Genet 2003, 4:587-597. recruitment, interview and evaluation, M-A. EK and FC 16. Terwilliger J, Ott J: Handbook of Human Genetic Linkage Balti- participated in the genotyping, ML is the principal inves- more:Johns Hopkins University Press; 1994. 17. Bhalla US, Ram PT, Iyengar R: MAP kinase phosphatase as a locus tigator of the clinical protocols, BG is the principal inves- of flexibility in a mitogen-activated protein kinase signaling tigator of the molecular protocols, ETT participated in network. Science 2002, 297:1018-1023. 18. Crozatier C, Farley S, Mansuy IM, Dumas S, Giros B, Tzavara ET: Cal- study design and coordination, participated in patient cineurin (protein phosphatase 2B) is involved in the mecha- interview and genotyping, collected data and wrote the nisms of action of antidepressants. Neuroscience 2007, manuscript. 144:1470-1476. Acknowledgements This work was supported by Insitut national de la Sante et de la Recherche Medicale (INSERM), Assistance Publique – Hopitaux de Paris (AP-HP), AP- HP/INSERM contrat d'interface (to E.T.T), Agence National pour la Recher- che (ANR-Project ManageBP), Fondation pour la Recherche sur le Cer- veau, and National Alliance for Research on Schizophrenia and Depression. Written informed consent was obtained for research and publication from Publish with Bio Med Central and every the patients and/or their relatives. scientist can read your work free of charge "BioMed Central will be the most significant development for References disseminating the results of biomedical researc h in our lifetime." 1. Xia Z, Storm DR: The role of calmodulin as a signal integrator Sir Paul Nurse, Cancer Research UK for synaptic plasticity. Nat Rev Neurosci 2005, 6:267-276. 2. Gerber DJ, Hall D, Miyakawa T, Demars S, Gogos JA, Karayiorgou M, Your research papers will be: Tonegawa S: Evidence for association of schizophrenia with available free of charge to the entire biomedical community genetic variation in the 8p21.3 gene, PPP3CC, encoding the calcineurin gamma subunit. Proc Natl Acad Sci U S A 2003, peer reviewed and published immediately upon acceptance 100:8993-8998. cited in PubMed and archived on PubMed Central 3. Kinoshita Y, Suzuki T, Ikeda M, Kitajima T, Yamanouchi Y, Inada T, Yoneda H, Iwata N, Ozaki N: No association with the calcineurin yours — you keep the copyright A gamma subunit gene (PPP3CC) haplotype to Japanese BioMedcentral Submit your manuscript here: schizophrenia. J Neural Transm 2005, 112:1255-1262. http://www.biomedcentral.com/info/publishing_adv.asp Page 4 of 4 (page number not for citation purposes)

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