Abstract
Several investigations have suggested that disruption of circadian rhythms may provide the foundation for the development of mood disorders such as bipolar disorder (BP) and major depressive disorder (MDD). Recent animal studies reported that prokineticin 2 or prokineticin 2 receptor gene deficient mice showed disruptions in circadian and homeostatic regulation of sleep. This evidence indicates that prokineticin 2 gene (PROK2) and prokineticin 2 receptor gene (PROKR2) are good candidate genes for the pathogenesis of mood disorders. To evaluate the association between PROK2, PROKR2, and mood disorders, we conducted a case-control study of Japanese samples (151 bipolar patients, 319 major depressive disorder patients, and 340 controls) with four and five tagging SNPs in PROK2 or PROKR2, respectively, selected by HapMap database. We detected a significant association between PROKR2 and major depressive disorder and bipolar disorder in the Japanese population. In conclusion, our findings suggest that PROKR2 may play a role in the pathophysiology of mood disorders in the Japanese population. However, because our samples were small, it will be important to replicate and confirm these findings in other independent studies using larger samples.
This is a preview of subscription content, access via your institution.


References
Barnard, A. R., & Nolan, P. M. (2008). When clocks go bad: Neurobehavioural consequences of disrupted circadian timing. PLoS Genetics, 4(5), e1000040. doi:10.1371/journal.pgen.1000040.
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. doi:10.1093/bioinformatics/bth457.
Boivin, D. B. (2000). Influence of sleep-wake and circadian rhythm disturbances in psychiatric disorders. Journal of Psychiatry and Neuroscience, 25(5), 446–458.
Bowden, C. L. (2001). Strategies to reduce misdiagnosis of bipolar depression. Psychiatric Services, 52(1), 51–55. doi:10.1176/appi.ps.52.1.51.
Cheng, M. Y., Bullock, C. M., Li, C., Lee, A. G., Bermak, J. C., Belluzzi, J., et al. (2002). Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus. Nature, 417(6887), 405–410. doi:10.1038/417405a.
Currier, D., Mann, M. J., Oquendo, M. A., Galfalvy, H., & Mann, J. J. (2006). Sex differences in the familial transmission of mood disorders. Journal of Affective Disorders, 95(1–3), 51–60. doi:10.1016/j.jad.2006.04.014.
Dagan, Y., Stein, D., Steinbock, M., Yovel, I., & Hallis, D. (1998). Frequency of delayed sleep phase syndrome among hospitalized adolescent psychiatric patients. Journal of Psychosomatic Research, 45(1), 15–20.
Detera-Wadleigh, S. D., Badner, J. A., Yoshikawa, T., Sanders, A. R., Goldin, L. R., Turner, G., et al. (1997). Initial genome scan of the NIMH genetics initiative bipolar pedigrees: chromosomes 4, 7, 9, 18, 19, 20, and 21q. American Journal of Medical Genetics, 74(3), 254–262. doi:10.1002/(SICI)1096-8628(19970531)74:3<254::AID-AJMG4>3.0.CO;2-Q.
Dudbridge, F. (2003). Pedigree disequilibrium tests for multilocus haplotypes. Genetic Epidemiology, 25(2), 115–121. doi:10.1002/gepi.10252.
Fanous, A. H., Neale, M. C., Webb, B. T., Straub, R. E., O’Neill, F. A., Walsh, D., et al. (2008). Novel linkage to chromosome 20p using latent classes of psychotic illness in 270 Irish high-density families. Biological Psychiatry, 64(2), 121–127. doi:10.1016/j.biopsych.2007.11.023.
Faraone, S. V., Lyons, M. J., & Tsuang, M. T. (1987). Sex differences in affective disorder: Genetic transmission. Genetic Epidemiology, 4(5), 331–343. doi:10.1002/gepi.1370040503.
Hahn, L. W., Ritchie, M. D., & Moore, J. H. (2003). Multifactor dimensionality reduction software for detecting gene-gene and gene-environment interactions. Bioinformatics, 19(3), 376–382. doi:10.1093/bioinformatics/btf869.
Hu, W. P., Li, J. D., Zhang, C., Boehmer, L., Siegel, J. M., & Zhou, Q. Y. (2007). Altered circadian and homeostatic sleep regulation in prokineticin 2-deficient mice. Sleep, 30(3), 247–256.
Kishi, T., Ikeda, M., Kitajima, T., Suzuki, T., Yamanouchi, Y., Kinoshita, Y., et al. (2008a). No association between prostate apoptosis response 4 gene (PAWR) in schizophrenia and mood disorders in a Japanese population. American Journal of Medical Genetics B Neuropsychiatric Genetics, 147B(4), 531–534. doi:10.1002/ajmg.b.30634.
Kishi, T., Kitajima, T., Ikeda, M., Yamanouchi, Y., Kinoshita, Y., Kawashima, K., et al. (2009b). CLOCK may predict the response to fluvoxamine treatment in Japanese major depressive disorder patients. Neuromolecular Medicine, in press.
Kishi, T., Kitajima, T., Ikeda, M., Yamanouchi, Y., Kinoshita, Y., Kawashima, K., et al. (2009a). 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. doi:10.1007/s00406-009-0869-4.
Kishi, T., Kitajima, T., Ikeda, M., Yamanouchi, Y., Kinoshita, Y., Kawashima, K., et al. (2008b). Association analysis of nuclear receptor Rev-erb alpha gene (NR1D1) with mood disorders in the Japanese population. Neuroscience Research, 62(4), 211–215. doi:10.1016/j.neures.2008.08.008.
Lehnkering, H., & Siegmund, R. (2007). Influence of chronotype, season, and sex of subject on sleep behavior of young adults. Chronobiology International, 24(5), 875–888. doi:10.1080/07420520701648259.
Li, J. D., Hu, W. P., Boehmer, L., Cheng, M. Y., Lee, A. G., Jilek, A., et al. (2006). Attenuated circadian rhythms in mice lacking the prokineticin 2 gene. Journal of Neuroscience, 26(45), 11615–11623. doi:10.1523/JNEUROSCI.3679-06.2006.
Li, J. D., Hu, W. P., & Zhou, Q. Y. (2009). Disruption of the circadian output molecule prokineticin 2 results in anxiolytic and antidepressant-like effects in mice. Neuropsychopharmacology, 34(2), 367–373. doi:10.1038/npp.2008.61.
Mansour, H. A., Monk, T. H., & Nimgaonkar, V. L. (2005). Circadian genes and bipolar disorder. Annals of Medicine, 37(3), 196–205. doi:10.1080/07853890510007377.
McClung, C. A. (2007a). Circadian genes, rhythms and the biology of mood disorders. Pharmacology and Therapeutics, 114(2), 222–232. doi:10.1016/j.pharmthera.2007.02.003.
McClung, C. A. (2007b). Role for the Clock gene in bipolar disorder. Cold Spring Harbor Symposia on Quantitative Biology, 72, 637–644. doi:10.1101/sqb.2007.72.031.
O’Donovan, M. C., Craddock, N., Norton, N., Williams, H., Peirce, T., Moskvina, V., et al. (2008). Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nature Genetics, in press.
Prosser, H. M., Bradley, A., Chesham, J. E., Ebling, F. J., Hastings, M. H., & Maywood, E. S. (2007). Prokineticin receptor 2 (Prokr2) is essential for the regulation of circadian behavior by the suprachiasmatic nuclei. Proceedings of the National Academy of Sciences of the United States of America, 104(2), 648–653. doi:10.1073/pnas.0606884104.
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. doi:10.1093/bioinformatics/19.1.149.
Ross, J., Berrettini, W., Coryell, W., Gershon, E. S., Badner, J. A., Kelsoe, J. R., et al. (2008). Genome-wide parametric linkage analyses of 644 bipolar pedigrees suggest susceptibility loci at chromosomes 16 and 20. Psychiatric Genetics, 18(4), 191–198. doi:10.1097/YPG.0b013e3283050aa5.
Szczepankiewicz, A., Skibinska, M., Hauser, J., Slopien, A., Leszczynska-Rodziewicz, A., Kapelski, P., et al. (2006). Association analysis of the GSK-3beta T-50C gene polymorphism with schizophrenia and bipolar disorder. Neuropsychobiology, 53(1), 51–56. doi:10.1159/000090704.
Wirz-Justice, A. (2006). Biological rhythm disturbances in mood disorders. International Clinical Psychopharmacology, 21(Suppl 1), S11–S15. doi:10.1097/01.yic.0000195660.37267.cf.
Zhou, Q. Y., & Cheng, M. Y. (2005). Prokineticin 2 and circadian clock output. FEBS Journal, 272(22), 5703–5709. doi:10.1111/j.1742-4658.2005.04984.x.
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).
Author information
Authors and Affiliations
Corresponding author
Additional information
Taro Kishi and Tsuyoshi Kitajima participated equally in this work.
Rights and permissions
About this article
Cite this article
Kishi, T., Kitajima, T., Tsunoka, T. et al. Possible Association of Prokineticin 2 Receptor Gene (PROKR2) with Mood Disorders in the Japanese Population. Neuromol Med 11, 114–122 (2009). https://doi.org/10.1007/s12017-009-8067-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12017-009-8067-0