Background: Bipolar disorder (BPD) is a common and severe mental disorder. The involvement of genetic factors in the pathophysiology of BPD is well known. In the present study, we tested the association of several single-nucleotide polymorphisms (SNPs) within 3 strong candidate genes (CACNA1C, CHRNA7, and MAPK1) with BPD. These genes are involved in monoamine-related pathways, as well as in dendrite development, neuronal survival, synaptic plasticity, and memory/learning. Methods: One hundred and thirty-two subjects diagnosed with BPD and 326 healthy controls of Korean ancestry were genotyped for 40 SNPs within CACNA1C, CHRNA17, and MAPK1. Distribution of alleles and block of haplotypes within each gene were compared in cases and controls. Interactions between variants in different loci were also tested. Results: Significant differences in the distribution of alleles between the cases and controls were detected for rs1016388 within CACNA1C, rs1514250, rs2337980, rs6494223, rs3826029 and rs4779565 within CHRNA7, and rs8136867 within MAPK1. Haplotype analyses also confirmed an involvement of variations within these genes in BPD. Finally, exploratory epistatic analyses demonstrated potential interactive effects, especially regarding variations in CACNA1C and CHRNA7. Limitations: Limited sample size and risk of false-positive findings. Discussion: Our data suggest a possible role of these 3 genes in BPD. Alterations of 1 or more common brain pathways (e.g., neurodevelopment and neuroplasticity, calcium signaling) may explain the obtained results.

1.
Kleine-Budde K, Touil E, Moock J, Bramesfeld A, Kawohl W, Rossler W: Cost of illness for bipolar disorder: a systematic review of the economic burden. Bipolar Disord 2014;16:337-353.
2.
Abell S, Ey JL: Bipolar disorder. Clin Pediatr (Phila) 2009;48:693-694.
3.
Sullivan PF, Daly MJ, O'Donovan M: Genetic architectures of psychiatric disorders: the emerging picture and its implications. Nat Rev Genet 2012;13:537-551.
4.
Oedegaard KJ, Alda M, Anand A, Andreassen OA, Balaraman Y, Berrettini WH, Bhattacharjee A, Brennand KJ, Burdick KE, Calabrese JR, Calkin CV, Claasen A, Coryell WH, Craig D, DeModena A, Frye M, Gage FH, Gao K, Garnham J, Gershon E, Jakobsen P, Leckband SG, McCarthy MJ, McInnis MG, Maihofer AX, Mertens J, Morken G, Nievergelt CM, Nurnberger J, Pham S, Schoeyen H, Shekhtman T, Shilling PD, Szelinger S, Tarwater B, Yao J, Zandi PP, Kelsoe JR: The Pharmacogenomics of Bipolar Disorder study (PGBD): identification of genes for lithium response in a prospective sample. BMC Psychiatry 2016;16:129.
5.
Smith DJ, Escott-Price V, Davies G, Bailey ME, Colodro-Conde L, Ward J, Vedernikov A, Marioni R, Cullen B, Lyall D, Hagenaars SP, Liewald DC, Luciano M, Gale CR, Ritchie SJ, Hayward C, Nicholl B, Bulik-Sullivan B, Adams M, Couvy-Duchesne B, Graham N, Mackay D, Evans J, Smith BH, Porteous DJ, Medland SE, Martin NG, Holmans P, McIntosh AM, Pell JP, Deary IJ, O'Donovan MC: Genome-wide analysis of over 106,000 individuals identifies 9 neuroticism-associated loci. Mol Psychiatry 2016;21:749-757.
6.
Mallas EJ, Carletti F, Chaddock CA, Woolley J, Picchioni MM, Shergill SS, Kane F, Allin MP, Barker GJ, Prata DP: Genome-wide discovered psychosis-risk gene ZNF804A impacts on white matter microstructure in health, schizophrenia and bipolar disorder. Peer J 2016;4:e1570.
7.
Angst J, Sellaro R: Historical perspectives and natural history of bipolar disorder. Biol Psychiatry 2000;48:445-457.
8.
Berk M, Dodd S: Efficacy of atypical antipsychotics in bipolar disorder. Drugs 2005;65:257-269.
9.
Berk M, Kapczinski F, Andreazza AC, Dean OM, Giorlando F, Maes M, Yucel M, Gama CS, Dodd S, Dean B, Magalhaes PV, Amminger P, McGorry P, Malhi GS: Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neurosci Biobehav Rev 2011;35:804-817.
10.
Fabbri C, Marsano A, Albani D, Chierchia A, Calati R, Drago A, Crisafulli C, Calabro M, Kasper S, Lanzenberger R, Zohar J, Juven-Wetzler A, Souery D, Montgomery S, Mendlewicz J, Serretti A: PPP3CC gene: a putative modulator of antidepressant response through the B-cell receptor signaling pathway. Pharmacogenomics J 2014;14:463-472.
11.
Drago A, Crisafulli C, Sidoti A, Serretti A: The molecular interaction between the glutamatergic, noradrenergic, dopaminergic and serotoninergic systems informs a detailed genetic perspective on depressive phenotypes. Prog Neurobiol 2011;94:418-460.
12.
Ancin I, Cabranes JA, Santos JL, Sanchez-Morla E, Vazquez-Alvarez B, Rodriguez-Moya L, Pousada-Casal A, Fernandez C, Aparicio A, Barabash A: CHRNA7 haplotypes are associated with impaired attention in euthymic bipolar disorder. J Affect Disord 2011;133:340-345.
13.
Lett TA, Zai CC, Tiwari AK, Shaikh SA, Likhodi O, Kennedy JL, Muller DJ: ANK3, CACNA1C and ZNF804A gene variants in bipolar disorders and psychosis subphenotype. World J Biol Psychiatry 2011;12:392-397.
14.
Chen HM, DeLong CJ, Bame M, Rajapakse I, Herron TJ, McInnis MG, O'Shea KS: Transcripts involved in calcium signaling and telencephalic neuronal fate are altered in induced pluripotent stem cells from bipolar disorder patients. Transl Psychiatry 2014;4:e375.
15.
Viswanath B, Jose SP, Squassina A, Thirthalli J, Purushottam M, Mukherjee O, Vladimirov V, Patrinos GP, Del Zompo M, Jain S: Cellular models to study bipolar disorder: a systematic review. J Affect Disord 2015;184:36-50.
16.
O'Shea KS, McInnis MG: Neurodevelopmental origins of bipolar disorder: iPSC models. Mol Cell Neurosci 2016;73:63-83.
17.
Garcia-Fuster MJ, Diez-Alarcia R, Ferrer-Alcon M, La Harpe R, Meana JJ, Garcia-Sevilla JA: FADD adaptor and PEA-15/ERK1/2 partners in major depression and schizophrenia postmortem brains: basal contents and effects of psychotropic treatments. Neuroscience 2014;277:541-551.
18.
Calati R, Crisafulli C, Balestri M, Serretti A, Spina E, Calabro M, Sidoti A, Albani D, Massat I, Hofer P, Amital D, Juven-Wetzler A, Kasper S, Zohar J, Souery D, Montgomery S, Mendlewicz J: Evaluation of the role of MAPK1 and CREB1 polymorphisms on treatment resistance, response and remission in mood disorder patients. Prog Neuropsychopharmacol Biol Psychiatry 2013;44:271-278.
19.
Krishnan V, Nestler EJ: Linking molecules to mood: new insight into the biology of depression. Am J Psychiatry 2010;167:1305-1320.
20.
Vogelzangs N, Duivis HE, Beekman AT, Kluft C, Neuteboom J, Hoogendijk W, Smit JH, de Jonge P, Penninx BW: Association of depressive disorders, depression characteristics and antidepressant medication with inflammation. Transl Psychiatry 2012;2:e79.
21.
Zunszain PA, Hepgul N, Pariante CM: Inflammation and depression. Curr Top Behav Neurosci 2013;14:135-151.
22.
Kamei H, Nagai T, Nakano H, Togan Y, Takayanagi M, Takahashi K, Kobayashi K, Yoshida S, Maeda K, Takuma K, Nabeshima T, Yamada K: Repeated methamphetamine treatment impairs recognition memory through a failure of novelty-induced ERK1/2 activation in the prefrontal cortex of mice. Biol Psychiatry 2006;59:75-84.
23.
Ishii D, Matsuzawa D, Kanahara N, Matsuda S, Sutoh C, Ohtsuka H, Nakazawa K, Kohno M, Hashimoto K, Iyo M, Shimizu E: Effects of aripiprazole on MK-801-induced prepulse inhibition deficits and mitogen-activated protein kinase signal transduction pathway. Neurosci Lett 2010;471:53-57.
24.
Yuan P, Zhou R, Wang Y, Li X, Li J, Chen G, Guitart X, Manji HK: Altered levels of extracellular signal-regulated kinase signaling proteins in postmortem frontal cortex of individuals with mood disorders and schizophrenia. J Affect Disord 2010;124:164-169.
25.
Wellcome Trust Case Control C: Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007;447:661-678.
26.
Ferreira MA, O'Donovan MC, Meng YA, Jones IR, Ruderfer DM, Jones L, Fan J, Kirov G, Perlis RH, Green EK, Smoller JW, Grozeva D, Stone J, Nikolov I, Chambert K, Hamshere ML, Nimgaonkar VL, Moskvina V, Thase ME, Caesar S, Sachs GS, Franklin J, Gordon-Smith K, Ardlie KG, Gabriel SB, Fraser C, Blumenstiel B, Defelice M, et al; Wellcome Trust Case Control Consortium: Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 2008;40:1056-1058.
27.
Sklar P, Smoller JW, Fan J, Ferreira MA, Perlis RH, Chambert K, Nimgaonkar VL, McQueen MB, Faraone SV, Kirby A, de Bakker PI, Ogdie MN, Thase ME, Sachs GS, Todd-Brown K, Gabriel SB, Sougnez C, Gates C, Blumenstiel B, Defelice M, Ardlie KG, Franklin J, Muir WJ, McGhee KA, MacIntyre DJ, McLean A, VanBeck M, McQuillin A, Bass NJ, Robinson M, Lawrence J, Anjorin A, Curtis D, et al: Whole-genome association study of bipolar disorder. Mol Psychiatry 2008;13:558-569.
28.
Wray NR, Pergadia ML, Blackwood DH, Penninx BW, Gordon SD, Nyholt DR, Ripke S, MacIntyre DJ, McGhee KA, Maclean AW, Smit JH, Hottenga JJ, Willemsen G, Middeldorp CM, de Geus EJ, Lewis CM, McGuffin P, Hickie IB, van den Oord EJ, Liu JZ, Macgregor S, McEvoy BP, Byrne EM, Medland SE, Statham DJ, Henders AK, Heath AC, Montgomery GW, Martin NG, et al: Genome-wide association study of major depressive disorder: new results, meta-analysis, and lessons learned. Mol Psychiatry 2012;17:36-48.
29.
Ancin I, Barabash A, Vazquez-Alvarez B, Santos JL, Sanchez-Morla E, Martinez JL, Aparicio A, Pelaez JC, Diaz JA: Evidence for association of the non-duplicated region of CHRNA7 gene with bipolar disorder but not with schizophrenia. Psychiatr Genet 2010;20:289-297.
30.
Flomen RH, Collier DA, Osborne S, Munro J, Breen G, St Clair D, Makoff AJ: Association study of CHRFAM7A copy number and 2 bp deletion polymorphisms with schizophrenia and bipolar affective disorder. Am J Med Genet B Neuropsychiatr Genet 2006;141B: 571-575.
31.
Philip NS, Carpenter LL, Tyrka AR, Whiteley LB, Price LH: Varenicline augmentation in depressed smokers: an 8-week, open-label study. J Clin Psychiatry 2009;70:1026-1031.
32.
Rabenstein RL, Caldarone BJ, Picciotto MR: The nicotinic antagonist mecamylamine has antidepressant-like effects in wild-type but not beta2- or alpha7-nicotinic acetylcholine receptor subunit knockout mice. Psychopharmacology (Berl) 2006;189:395-401.
33.
Shytle RD, Silver AA, Lukas RJ, Newman MB, Sheehan DV, Sanberg PR: Nicotinic acetylcholine receptors as targets for antidepressants. Mol Psychiatry 2002;7:525-535.
34.
Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC: The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998;59(suppl 20):22-33; quiz 34-57.
35.
Barrett JC, Fry B, Maller J, Daly MJ: Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005;21:263-265.
36.
Benjamini Y, Drai D, Elmer G, Kafkafi N, Golani I: Controlling the false discovery rate in behavior genetics research. Behav Brain Res 2001;125:279-284.
37.
Van Steen K, Lange C: PBAT: a comprehensive software package for genome-wide association analysis of complex family-based studies. Hum Genomics 2005;2:67-69.
38.
Rosand J: Epistasis is coming: are we ready? Stroke 2005;36:1879-1880.
39.
Psychiatric GWAS Consortium Bipolar Disorder Working Group: Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat Genet 2011;43:977-983.
40.
Wessa M, Linke J, Witt SH, Nieratschker V, Esslinger C, Kirsch P, Grimm O, Hennerici MG, Gass A, King AV, Rietschel M: The CACNA1C risk variant for bipolar disorder influences limbic activity. Mol Psychiatry 2010;15:1126-1127.
41.
Jogia J, Ruberto G, Lelli-Chiesa G, Vassos E, Maieru M, Tatarelli R, Girardi P, Collier D, Frangou S: The impact of the CACNA1C gene polymorphism on frontolimbic function in bipolar disorder. Mol Psychiatry 2011;16:1070-1071.
42.
Bigos KL, Mattay VS, Callicott JH, Straub RE, Vakkalanka R, Kolachana B, Hyde TM, Lipska BK, Kleinman JE, Weinberger DR: Genetic variation in CACNA1C affects brain circuitries related to mental illness. Arch Gen Psychiatry 2010;67:939-945.
43.
Tesli M, Skatun KC, Ousdal OT, Brown AA, Thoresen C, Agartz I, Melle I, Djurovic S, Jensen J, Andreassen OA: CACNA1C risk variant and amygdala activity in bipolar disorder, schizophrenia and healthy controls. PLoS One 2013;8:e56970.
44.
Shi J, Hattori E, Zou H, Badner JA, Christian SL, Gershon ES, Liu C: No evidence for association between 19 cholinergic genes and bipolar disorder. Am J Med Genet B Neuropsychiatr Genet 2007;144B:715-723.
45.
Joo EJ, Lee KY, Kim HS, Kim SH, Ahn YM, Kim YS: Genetic association study of the alpha 7 nicotinic receptor (CHRNA7) with the development of schizophrenia and bipolar disorder in Korean population. Psychiatry Investig 2010;7:196-201.
46.
Gillentine MA, Schaaf CP: The human clinical phenotypes of altered CHRNA7 copy number. Biochem Pharmacol 2015;97:352-362.
47.
Chuang DM, Chen RW, Chalecka-Franaszek E, Ren M, Hashimoto R, Senatorov V, Kanai H, Hough C, Hiroi T, Leeds P: Neuroprotective effects of lithium in cultured cells and animal models of diseases. Bipolar Disord 2002;4:129-136.
48.
Eckel-Mahan KL, Phan T, Han S, Wang H, Chan GC, Scheiner ZS, Storm DR: Circadian oscillation of hippocampal MAPK activity and cAmp: implications for memory persistence. Nat Neurosci 2008;11:1074-1082.
49.
Samuels IS, Saitta SC, Landreth GE: MAP'ing CNS development and cognition: an ERKsome process. Neuron 2009;61:160-167.
50.
Bozon B, Kelly A, Josselyn SA, Silva AJ, Davis S, Laroche S: MAPK, CREB and zif268 are all required for the consolidation of recognition memory. Philos Trans R Soc Lond B Biol Sci 2003;358:805-814.
51.
English JD, Sweatt JD: Activation of p42 mitogen-activated protein kinase in hippocampal long term potentiation. J Biol Chem 1996;271:24329-24332.
52.
Smedlund K, Tano JY, Margiotta J, Vazquez G: Evidence for operation of nicotinic and muscarinic acetylcholine receptor-dependent survival pathways in human coronary artery endothelial cells. J Cell Biochem 2011;112:1978-1984.
53.
Apati A, Janossy J, Brozik A, Bauer PI, Magocsi M: Calcium induces cell survival and proliferation through the activation of the MAPK pathway in a human hormone-dependent leukemia cell line, TF-1. J Biol Chem 2003;278:9235-9243.
54.
Apati A, Janossy J, Brozik A, Magocsi M: Effects of intracellular calcium on cell survival and the MAPK pathway in a human hormone-dependent leukemia cell line (TF-1). Ann NY Acad Sci 2003;1010:70-73.
55.
Goes FS: Genetics of bipolar disorder: recent update and future directions. Psychiatr Clin North Am 2016;39:139-155.
56.
Fiorentino A, O'Brien NL, Locke DP, McQuillin A, Jarram A, Anjorin A, Kandaswamy R, Curtis D, Blizard RA, Gurling HM: Analysis of ANK3 and CACNA1C variants identified in bipolar disorder whole genome sequence data. Bipolar Disord 2014;16:583-591.
57.
Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A, Fridman WH, Pagès F, Trajanoski Z, Galon J: ClueGO: a cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics 2009;25:1091-1093.
58.
Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T: Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 2003;13: 2498-2504.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.