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Lack of Association Between MAGEL2 and Schizophrenia and Mood Disorders in the Japanese Population

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Abstract

Several investigations have reported that abnormalities in circadian rhythms might be related with the pathophysiology of psychiatric disorders, since many psychiatric patients have insomnia and sleep-awake disturbance. A recent animal study reported that Magel2, which encodes a member of the MAGE/necdin family of proteins, might be associated in the pathophysiology of psychiatric disorders. Magel2 gene knockout mice showed altered concentrations of both dopamine and serotonin in several parts of the brain compared with controls. In addition, the authors of that study detected a bilateral reduction in cortical volume in distinct regions of the Magel2 gene knockout mice brain, including focused regions in the parieto-temporal lobe of the cerebral cortex, the amygdala, the hippocampus, and the nucleus accumbens. These mice were also found to have hypoactivity and abnormalities in circadian rhythms. From this evidence, we considered Magel2 gene (MAGEL2) to be a good candidate gene for the pathophysiology of schizophrenia and mood disorder, and we conducted a case–control study among Japanese (731 schizophrenia patients, 465 MDD patients, 156 BP patients and 758 controls) using three tagging SNPs in MAGEL2 (rs850815, rs8920 and rs4480754), selected using the HapMap database. We did not find any association between MAGEL2 and schizophrenia, BP or MDD in allele/genotype-wise analysis or haplotype-wise analysis. Our results suggest that MAGEL2 may not play a role in the pathophysiology of schizophrenia and mood disorders in the Japanese population. A replication study using larger samples may be required for conclusive results, since our sample size was small and our study analyzed only three SNPs in MAGEL2.

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References

  • Abe, O., Yamasue, H., Kasai, K., Yamada, H., Aoki, S., Inoue, H., et al. (2010). Voxel-based analyses of gray/white matter volume and diffusion tensor data in major depression. Psychiatry Research, 181(1), 64–70.

    Article  PubMed  Google Scholar 

  • Barbini, B., Benedetti, F., Colombo, C., Guglielmo, E., Campori, E., & Smeraldi, E. (1998). Perceived mood and skin body temperature rhythm in depression. European Archives of Psychiatry and Clinical Neuroscience, 248(3), 157–160.

    Article  CAS  PubMed  Google Scholar 

  • Barnard, A. R., & Nolan, P. M. (2008). When clocks go bad: neurobehavioural consequences of disrupted circadian timing. PLoS Genet, 4(5), e1000040.

    Article  PubMed  Google Scholar 

  • Barrett, J. C., Fry, B., Maller, J., & Daly, M. J. (2005). Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics, 21(2), 263–265.

    Article  CAS  PubMed  Google Scholar 

  • Berk, M., Dodd, S., Kauer-Sant’anna, M., Malhi, G. S., Bourin, M., Kapczinski, F., et al. (2007). Dopamine dysregulation syndrome: implications for a dopamine hypothesis of bipolar disorder. Acta Psychiatrica Scandinavica. Supplementum, 434, 41–49.

    Article  PubMed  Google Scholar 

  • Bischof, J. M., Stewart, C. L., & Wevrick, R. (2007). Inactivation of the mouse Magel2 gene results in growth abnormalities similar to Prader-Willi syndrome. Human Molecular Genetics, 16(22), 2713–2719.

    Article  CAS  PubMed  Google Scholar 

  • Bora, E., Yucel, M., & Allen, N. B. (2009). Neurobiology of human affiliative behaviour: Implications for psychiatric disorders. Current Opinion in Psychiatry, 22(3), 320–325.

    Article  PubMed  Google Scholar 

  • Bowden, C. L. (2001). Strategies to reduce misdiagnosis of bipolar depression. Psychiatric Services, 52(1), 51–55.

    Article  CAS  PubMed  Google Scholar 

  • Brambilla, P., Hatch, J. P., & Soares, J. C. (2008). Limbic changes identified by imaging in bipolar patients. Current Psychiatry Reports, 10(6), 505–509.

    Article  PubMed  Google Scholar 

  • Brunet-Gouet, E., & Decety, J. (2006). Social brain dysfunctions in schizophrenia: a review of neuroimaging studies. Psychiatry Research, 148(2–3), 75–92.

    Article  PubMed  Google Scholar 

  • Depienne, C., Moreno-De-Luca, D., Heron, D., Bouteiller, D., Gennetier, A., Delorme, R., et al. (2009). Screening for genomic rearrangements and methylation abnormalities of the 15q11–q13 region in autism spectrum disorders. Biological Psychiatry, 66(4), 349–359.

    Article  CAS  PubMed  Google Scholar 

  • Dudbridge, F. (2003). Pedigree disequilibrium tests for multilocus haplotypes. Genetic Epidemiology, 25(2), 115–121.

    Article  PubMed  Google Scholar 

  • Feng, Y., Vetro, A., Kiss, E., Kapornai, K., Daroczi, G., Mayer, L., et al. (2008). Association of the neurotrophic tyrosine kinase receptor 3 (NTRK3) gene and childhood-onset mood disorders. American Journal of Psychiatry, 165(5), 610–616.

    Article  PubMed  Google Scholar 

  • Hogart, A., Wu, D., Lasalle, J. M., & Schanen, N. C. (2008). The comorbidity of autism with the genomic disorders of chromosome 15q11.2–q13. Neurobiology of Disease, 38(2), 181–191.

    Article  PubMed  Google Scholar 

  • Ikeda, M., Aleksic, B., Kirov, G., Kinoshita, Y., Yamanouchi, Y., Kitajima, T., et al. (2009). Copy number variation in schizophrenia in the Japanese population. Biological Psychiatry, 67(3), 283–286.

    Article  PubMed  Google Scholar 

  • Kanber, D., Giltay, J., Wieczorek, D., Zogel, C., Hochstenbach, R., Caliebe, A., et al. (2009). A paternal deletion of MKRN3, MAGEL2 and NDN does not result in Prader-Willi syndrome. European Journal of Human Genetics, 17(5), 582–590.

    Article  CAS  PubMed  Google Scholar 

  • Kim, S. J., Brune, C. W., Kistner, E. O., Christian, S. L., Courchesne, E. H., Cox, N. J., et al. (2008). Transmission disequilibrium testing of the chromosome 15q11–q13 region in autism. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 147B(7), 1116–1125.

    Article  CAS  Google Scholar 

  • Kishi, T., Kitajima, T., Ikeda, M., Yamanouchi, Y., Kinoshita, Y., Kawashima, K., et al. (2008). Association analysis of nuclear receptor Rev-erb alpha gene (NR1D1) with mood disorders in the Japanese population. Neuroscience Research, 62(4), 211–215.

    Article  CAS  PubMed  Google Scholar 

  • Kishi, T., Ikeda, M., Kitajima, T., Yamanouchi, Y., Kinoshita, Y., Kawashima, K., et al. (2009a). Association analysis of functional polymorphism in estrogen receptor alpha gene with schizophrenia and mood disorders in the Japanese population. Psychiatric Genetics, 19(4), 217–218.

    Article  PubMed  Google Scholar 

  • Kishi, T., Ikeda, M., Kitajima, T., Yamanouchi, Y., Kinoshita, Y., Kawashima, K., et al. (2009b). A functional polymorphism in estrogen receptor alpha gene is associated with Japanese methamphetamine induced psychosis. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 33(5), 895–898.

    Article  CAS  PubMed  Google Scholar 

  • Kishi, T., Kitajima, T., Ikeda, M., Yamanouchi, Y., Kinoshita, Y., Kawashima, K., et al. (2009c). Association study of clock gene (CLOCK) and schizophrenia and mood disorders in the Japanese population. European Archives of Psychiatry and Clinical Neuroscience, 259(5), 293–297.

    Article  PubMed  Google Scholar 

  • Kishi, T., Kitajima, T., Ikeda, M., Yamanouchi, Y., Kinoshita, Y., Kawashima, K., et al. (2009d). CLOCK may predict the response to fluvoxamine treatment in Japanese major depressive disorder patients. Neuromolecular Medicine, 11(2), 53–57.

    Article  CAS  PubMed  Google Scholar 

  • Kishi, T., Kitajima, T., Ikeda, M., Yamanouchi, Y., Kinoshita, Y., Kawashima, K., et al. (2009e). Orphan nuclear receptor Rev-erb alpha gene (NR1D1) and fluvoxamine response in major depressive disorder in the Japanese population. Neuropsychobiology, 59(4), 234–238.

    Article  CAS  PubMed  Google Scholar 

  • Kishi, T., Kitajima, T., Tsunoka, T., Ikeda, M., Yamanouchi, Y., Kinoshita, Y., et al. (2009f). Genetic association analysis of serotonin 2A receptor gene (HTR2A) with bipolar disorder and major depressive disorder in the Japanese population. Neuroscience Research, 64(2), 231–234.

    Article  CAS  PubMed  Google Scholar 

  • Kishi, T., Kitajima, T., Tsunoka, T., Okumura, T., Ikeda, M., Okochi, T., et al. (2009g). Possible association of prokineticin 2 receptor gene (PROKR2) with mood disorders in the Japanese population. Neuromolecular Medicine, 11(2), 114–122.

    Article  CAS  PubMed  Google Scholar 

  • Kishi, T., Tsunoka, T., Ikeda, M., Kawashima, K., Okochi, T., Kitajima, T., et al. (2009h). Serotonin 1A receptor gene and major depressive disorder: an association study and meta-analysis. Journal of Human Genetics, 54(11), 629–633.

    Article  CAS  PubMed  Google Scholar 

  • Kishi, T., Yoshimura, R., Kitajima, T., Okochi, T., Okumura, T., Tsunoka, T., et al. (2009i). HTR2A is associated with SSRI response in major depressive disorder in a Japanese cohort. Neuromolecular Medicine, in press.

  • Kishi, T., Tsunoka, T., Ikeda, M., Kitajima, T., Kawashima, K., Okochi, T., et al. (2010). Serotonin 1A receptor gene is associated with Japanese methamphetamine-induced psychosis patients. Neuropharmacology, 58(2), 452–456.

    Article  CAS  PubMed  Google Scholar 

  • Konarski, J. Z., McIntyre, R. S., Kennedy, S. H., Rafi-Tari, S., Soczynska, J. K., & Ketter, T. A. (2008). Volumetric neuroimaging investigations in mood disorders: bipolar disorder versus major depressive disorder. Bipolar Disorders, 10(1), 1–37.

    Article  PubMed  Google Scholar 

  • Kozlov, S. V., Bogenpohl, J. W., Howell, M. P., Wevrick, R., Panda, S., Hogenesch, J. B., et al. (2007). The imprinted gene Magel2 regulates normal circadian output. Nature Genetics, 39(10), 1266–1272.

    Article  CAS  PubMed  Google Scholar 

  • Lang, U. E., Puls, I., Muller, D. J., Strutz-Seebohm, N., & Gallinat, J. (2007). Molecular mechanisms of schizophrenia. Cellular Physiology and Biochemistry, 20(6), 687–702.

    Article  CAS  PubMed  Google Scholar 

  • Maier, W., Hofgen, B., Zobel, A., & Rietschel, M. (2005). Genetic models of schizophrenia and bipolar disorder: overlapping inheritance or discrete genotypes? European Archives of Psychiatry and Clinical Neuroscience, 255(3), 159–166.

    Article  PubMed  Google Scholar 

  • Mansour, H. A., Talkowski, M. E., Wood, J., Chowdari, K. V., McClain, L., Prasad, K., et al. (2009). Association study of 21 circadian genes with bipolar I disorder, schizoaffective disorder, and schizophrenia. Bipolar Disorders, 11(7), 701–710.

    Article  CAS  PubMed  Google Scholar 

  • Mansour, H. A., Wood, J., Logue, T., Chowdari, K. V., Dayal, M., Kupfer, D. J., et al. (2006). Association study of eight circadian genes with bipolar I disorder, schizoaffective disorder and schizophrenia. Genes, Brain, and Behavior, 5(2), 150–157.

    Article  CAS  PubMed  Google Scholar 

  • McClung, C. A. (2007a). Circadian genes, rhythms and the biology of mood disorders. Pharmacology and Therapeutics, 114(2), 222–232.

    Article  CAS  PubMed  Google Scholar 

  • McClung, C. A. (2007b). Circadian rhythms, the mesolimbic dopaminergic circuit, and drug addiction. Scientific World Journal, 7, 194–202.

    PubMed  Google Scholar 

  • McClung, C. A. (2007c). Clock genes and bipolar disorder: Implications for therapy. Pharmacogenomics, 8(9), 1097–1100.

    Article  CAS  PubMed  Google Scholar 

  • McClung, C. A. (2007d). Role for the Clock gene in bipolar disorder. Cold Spring Harbor Symposia on Quantitative Biology, 72, 637–644.

    Article  CAS  PubMed  Google Scholar 

  • Mercer, R. E., Kwolek, E. M., Bischof, J. M., van Eede, M., Henkelman, R. M., & Wevrick, R. (2009). Regionally reduced brain volume, altered serotonin neurochemistry, and abnormal behavior in mice null for the circadian rhythm output gene Magel2. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 150B(8), 1085–1099.

    Article  CAS  Google Scholar 

  • Muller, N., & Schwarz, M. J. (2008). A psychoneuroimmunological perspective to Emil Kraepelins dichotomy: Schizophrenia and major depression as inflammatory CNS disorders. European Archives of Psychiatry and Clinical Neuroscience, 258(Suppl 2), 97–106.

    Article  PubMed  Google Scholar 

  • Nestler, E. J., & Carlezon, W. A., Jr. (2006). The mesolimbic dopamine reward circuit in depression. Biological Psychiatry, 59(12), 1151–1159.

    Article  CAS  PubMed  Google Scholar 

  • Nievergelt, C. M., Kripke, D. F., Barrett, T. B., Burg, E., Remick, R. A., Sadovnick, A. D., et al. (2006). Suggestive evidence for association of the circadian genes PERIOD3 and ARNTL with bipolar disorder. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 141B(3), 234–241.

    Article  CAS  Google Scholar 

  • Otnaess, M. K., Djurovic, S., Rimol, L. M., Kulle, B., Kahler, A. K., Jonsson, E. G., et al. (2009). Evidence for a possible association of neurotrophin receptor (NTRK-3) gene polymorphisms with hippocampal function and schizophrenia. Neurobiology of Diseases, 34(3), 518–524.

    Article  CAS  Google Scholar 

  • Purcell, S., Cherny, S. S., & Sham, P. C. (2003). Genetic power calculator: Design of linkage and association genetic mapping studies of complex traits. Bioinformatics, 19(1), 149–150.

    Article  CAS  PubMed  Google Scholar 

  • Savitz, J., Nugent, A. C., Bogers, W., Liu, A., Sills, R., Luckenbaugh, D. A., et al. (2010). Amygdala volume in depressed patients with bipolar disorder assessed using high resolution 3T MRI: the impact of medication. Neuroimage, 49(4), 2966–2976.

    Article  PubMed  Google Scholar 

  • Severino, G., Manchia, M., Contu, P., Squassina, A., Lampus, S., Ardau, R., et al. (2009). Association study in a Sardinian sample between bipolar disorder and the nuclear receptor REV-ERBalpha gene, a critical component of the circadian clock system. Bipolar Disorders, 11(2), 215–220.

    Article  PubMed  Google Scholar 

  • Soni, S., Whittington, J., Holland, A. J., Webb, T., Maina, E., Boer, H., et al. (2007). The course and outcome of psychiatric illness in people with Prader-Willi syndrome: implications for management and treatment. Journal of Intellectual Disability Research, 51(Pt 1), 32–42.

    Article  CAS  PubMed  Google Scholar 

  • Soni, S., Whittington, J., Holland, A. J., Webb, T., Maina, E. N., Boer, H., et al. (2008). The phenomenology and diagnosis of psychiatric illness in people with Prader-Willi syndrome. Psychological Medicine, 38(10), 1505–1514.

    Article  CAS  PubMed  Google Scholar 

  • Soria, V., Martinez-Amoros, E., Escaramis, G., Valero, J., Perez-Egea, R., Garcia, C., et al. (2010). Differential association of circadian genes with mood disorders: CRY1 and NPAS2 are associated with unipolar major depression and CLOCK and VIP with bipolar disorder. Neuropsychopharmacology, 35(6), 1279–1289.

    Article  CAS  PubMed  Google Scholar 

  • Stefansson, H., Rujescu, D., Cichon, S., Pietilainen, O. P., Ingason, A., Steinberg, S., et al. (2008). Large recurrent microdeletions associated with schizophrenia. Nature, 455(7210), 232–236.

    Article  CAS  PubMed  Google Scholar 

  • Stensland, M. D., Schultz, J. F., & Frytak, J. R. (2008). Diagnosis of unipolar depression following initial identification of bipolar disorder: a common and costly misdiagnosis. Journal of Clinical Psychiatry, 69(5), 749–758.

    Article  PubMed  Google Scholar 

  • van der Zwaag, B., Staal, W. G., Hochstenbach, R., Poot, M., Spierenburg, H. A., de Jonge, M. V., et al. (2009). A co-segregating microduplication of chromosome 15q11.2 pinpoints two risk genes for autism spectrum disorder. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, in press.

  • Verma, R., Holmans, P., Knowles, J. A., Grover, D., Evgrafov, O. V., Crowe, R. R., et al. (2008). Linkage disequilibrium mapping of a chromosome 15q25–26 major depression linkage region and sequencing of NTRK3. Biological Psychiatry, 63(12), 1185–1189.

    Article  CAS  PubMed  Google Scholar 

  • Voderholzer, U., Riemann, D., Huwig-Poppe, C., Kuelz, A. K., Kordon, A., Bruestle, K., et al. (2007). Sleep in obsessive compulsive disorder: polysomnographic studies under baseline conditions and after experimentally induced serotonin deficiency. European Archives of Psychiatry and Clinical Neuroscience, 257(3), 173–182.

    Article  PubMed  Google Scholar 

  • Williams, J. B. (1988). A structured interview guide for the Hamilton Depression Rating Scale. Archives of General Psychiatry, 45(8), 742–747.

    CAS  PubMed  Google Scholar 

  • Yamaguchi-Kabata, Y., Nakazono, K., Takahashi, A., Saito, S., Hosono, N., Kubo, M., et al. (2008). Japanese population structure, based on SNP genotypes from 7003 individuals compared to other ethnic groups: effects on population-based association studies. American Journal of Human Genetics, 83(4), 445–456.

    Article  CAS  PubMed  Google Scholar 

  • Yang, Y., Raine, A., Han, C. B., Schug, R. A., Toga, A. W., & Narr, K. L. (2010). Reduced hippocampal and parahippocampal volumes in murderers with schizophrenia. Psychiatry Research, 182(1), 9–13.

    Article  PubMed  Google Scholar 

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Acknowledgments

We thank Ms M Miyata and Ms S Ishihara for their technical support. This work was supported in part by research grants from the Ministry of Education, Culture, Sports, Science and Technology, the Ministry of Health, Labor and Welfare, and the Japan Health Sciences Foundation (Research on Health Sciences focusing on Drug Innovation).

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Authors and Affiliations

  1. Department of Pychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, 470-1192, Japan

    Yasuhisa Fukuo, Taro Kishi, Tomo Okochi, Tsuyoshi Kitajima, Tomoko Tsunoka, Takenori Okumukura, Yoko Kinoshita, Kunihiro Kawashima, Yoshio Yamanouchi, Hiroshi Naitoh & Nakao Iwata

  2. Department of Psychiatry, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, 807-8555, Japan

    Wakako Umene-Nakano, Reiji Yoshimura & Jun Nakamura

  3. Neuropsychiatric Research Institute, Seiwa Hospital, Tokyo, 162-0851, Japan

    Toshiya Inada

  4. Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, 466-8850, Japan

    Norio Ozaki

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  1. Yasuhisa Fukuo
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  2. Taro Kishi
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Correspondence to Taro Kishi.

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Yasuhisa Fukuo and Taro Kishi participated equally in this work.

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Fukuo, Y., Kishi, T., Okochi, T. et al. Lack of Association Between MAGEL2 and Schizophrenia and Mood Disorders in the Japanese Population. Neuromol Med 12, 285–291 (2010). https://doi.org/10.1007/s12017-010-8116-8

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