Insights into the origin of DNA methylation differences between monozygotic twins discordant for schizophrenia

Journal of Molecular Psychiatry - Tập 3 - Trang 1-10 - 2015
Melkaye G. Melka1, Christina A. Castellani1, Richard O’Reilly2, Shiva M. Singh1
1Molecular Genetics Unit, Western Science Centre, Department of Biology, The University of Western Ontario, London, Canada
2Department of Psychiatry, The University of Western Ontario, London, Canada

Tóm tắt

DNA methylation differences between monozygotic twins discordant for schizophrenia have been previously reported. However, the origin of methylation differences between monozygotic twins discordant for schizophrenia is not clear. The findings here argue that all DNA methylation differences may not necessarily represent the cause of the disease; rather some may result from the effect of antipsychotics. Methylation differences in rat brain regions and also in two pairs of unrelated monozygotic twins discordant for schizophrenia have been studied using genome-wide DNA methylation arrays at Arraystar Inc. (Rockville, Maryland, USA). The identified gene promoters showing significant alterations to DNA methylation were then further characterized using ingenuity pathway analysis (Ingenuity System Inc, CA, USA). Pathway analysis of the most significant gene promoter hyper/hypomethylation revealed a significant enrichment of DNA methylation changes in biological networks and pathways directly relevant to neural development and psychiatric disorders. These included HIPPO signaling (p = 3.93E-03) and MAPK signaling (p = 4.27E-03) pathways involving hypermethylated genes in schizophrenia-affected patients as compared to their unaffected co-twins. Also, a number of significant pathways and networks involving genes with hypomethylated gene promoters have been identified. These included CREB signaling in neurons (p = 1.53E-02), Dopamine-DARPP32 feedback in cAMP signaling (p = 7.43E-03) and Ephrin receptors (p = 1.13E-02). Further, there was significant enrichment for pathways involved in nervous system development and function (p = 1.71E-03-4.28E-02). The findings highlight the significance of antipsychotic drugs on DNA methylation in schizophrenia patients. The unique pathways affected by DNA methylation in the two pairs of monozygotic twins suggest that patient-specific pathways are responsible for the disease; suggesting that patient-specific treatment strategies may be necessary in treating the disorder. The study reflects the need for developing personalized medicine approaches that take into consideration epigenetic variations between patients.

Tài liệu tham khảo

Bosia M, Pigoni A, Cavallaro R. Genomics and epigenomics in novel schizophrenia drug discovery: translating animal models to clinical research and back. Expert Opin Drug Discov. 2015;10(2):125–39. Abdolmaleky HM, Smith CL, Zhou JR, Thiagalingam S. Epigenetic alterations of the dopaminergic system in major psychiatric disorders. Methods Mol Biol. 2008;448:187–212. Rosales-Reynoso MA, Ochoa-Hernandez AB, Juarez-Vazquez CI, Barros-Nunez P. Epigenetic mechanisms in the development of memory and their involvement in certain neurological diseases. Neurologia. 2014. doi:10.1016/j.nrl.2014.02.004. Gavin DP, Akbarian S. Epigenetic and post-transcriptional dysregulation of gene expression in schizophrenia and related disease. Neurobiol Dis. 2012;46(2):255–62. Razin A, Kantor B. DNA methylation in epigenetic control of gene expression. Prog Mol Subcell Biol. 2005;38:151–67. Abdolmaleky HM, Smith CL, Faraone SV, et al. Methylomics in psychiatry: modulation of gene-environment interactions may be through DNA methylation. Am J Med Genet B Neuropsychiatr Genet. 2004;127B(1):51–9. Singh SM, Murphy B, O’Reilly R. Epigenetic contributors to the discordance of monozygotic twins. Clin Genet. 2002;62(2):97–103. Petronis A, Gottesman II, Kan P, et al. Monozygotic twins exhibit numerous epigenetic differences: clues to twin discordance? Schizophr Bull. 2003;29(1):169–78. Petronis A. Epigenetics and twins: three variations on the theme. Trends Genet. 2006;22(7):347–50. Dempster EL, Pidsley R, Schalkwyk LC, et al. Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder. Hum Mol Genet. 2011;20(24):4786–96. Ollikainen M, Smith KR, Joo EJ, et al. DNA methylation analysis of multiple tissues from newborn twins reveals both genetic and intrauterine components to variation in the human neonatal epigenome. Hum Mol Genet. 2010;19(21):4176–88. Fraga MF, Esteller M. Towards the human cancer epigenome: a first draft of histone modifications. Cell Cycle. 2005;4(10):1377–81. Melka Melkaye G, Castellani Christina A, Laufer Benjamin I, Rajakumar N, O’Reilly R, Singh SM. Olanzapine induced DNA methylation changes support the dopamine hypothesis of psychosis. J Mol Psych. 2013;1(19):1–7. Castellani CA, Laufer BI, Melka MG, Diehl EJ, O’Reilly RL, Singh SM. DNA methylation differences in monozygotic twin pairs discordant for schizophrenia identifies psychosis related genes and networks. BMC Med Genomics. 2015;8, 17-015-0093-1. doi:10.1186/s12920-015-0093-1. Melka MG, Laufer BI, McDonald P, et al. The effects of olanzapine on genome-wide DNA methylation in the hippocampus and cerebellum. Clin Epigenetics.2014; 6(1), 1-7083-6-1. doi:10.1186/1868-7083-6-1. Dempster EL, Wong CC, Lester KJ, et al. Genome-wide methylomic analysis of monozygotic twins discordant for adolescent depression. Biol Psychiatry. 2014;76(12):977–83. van Dongen J, Ehli EA, Slieker RC, et al. Epigenetic variation in monozygotic twins: a genome-wide analysis of DNA methylation in buccal cells. Genes (Basel). 2014;5(2):347–65. Bonsch D, Wunschel M, Lenz B, Janssen G, Weisbrod M, Sauer H. Methylation matters? Decreased methylation status of genomic DNA in the blood of schizophrenic twins. Psychiatry Res. 2012;198(3):533–7. Foley DL, Mackinnon A, Watts GF, et al. Cardiometabolic risk indicators that distinguish adults with psychosis from the general population, by age and gender. PLoS One. 2013;8(12):e82606. Chen SF, Hu TM, Lan TH, Chiu HJ, Sheen LY, Loh EW. Severity of psychosis syndrome and change of metabolic abnormality in chronic schizophrenia patients: severe negative syndrome may be related to a distinct lipid pathophysiology. Eur Psychiatry. 2014;29(3):167–71. Lipina TV, Fletcher PJ, Lee FH, Wong AH, Roder JC. Disrupted-in-schizophrenia-1 Gln31Leu polymorphism results in social anhedonia associated with monoaminergic imbalance and reduction of CREB and beta-arrestin-1,2 in the nucleus accumbens in a mouse model of depression. Neuropsychopharmacology. 2013;38(3):423–36. Yu M, Li W, Luo S, et al. Folic acid stimulation of neural stem cell proliferation is associated with altered methylation profile of PI3K/Akt/CREB. J Nutr Biochem. 2014;25(4):496–502. Guidotti A, Auta J, Chen Y, et al. Epigenetic GABAergic targets in schizophrenia and bipolar disorder. Neuropharmacology. 2011;60(7–8):1007–16. Bagot RC, Zhang TY, Wen X, et al. Variations in postnatal maternal care and the epigenetic regulation of metabotropic glutamate receptor 1 expression and hippocampal function in the rat. Proc Natl Acad Sci U S A. 2012;109 Suppl 2:17200–7. Levesque ML, Casey KF, Szyf M, et al. Genome-wide DNA methylation variability in adolescent monozygotic twins followed since birth. Epigenetics. 2014;9(10):1410–22. Byrne EM, Carrillo-Roa T, Henders AK, et al. Monozygotic twins affected with major depressive disorder have greater variance in methylation than their unaffected co-twin. Transl Psychiatry. 2013;3:e269. Grace AA. Dopamine system dysregulation by the hippocampus: implications for the pathophysiology and treatment of schizophrenia. Neuropharmacology. 2012;62(3):1342–8. Madras BK. History of the discovery of the antipsychotic dopamine D2 receptor: a basis for the dopamine hypothesis of schizophrenia. J Hist Neurosci. 2013;22(1):62–78. Abdolmaleky HM, Nohesara S, Ghadirivasfi M, et al. DNA hypermethylation of serotonin transporter gene promoter in drug naive patients with schizophrenia. Schizophr Res. 2014;152(2–3):373–80. Rivollier F, Lotersztajn L, Chaumette B, Krebs MO, Kebir O. Epigenetics of schizophrenia: a review. Encephale. 2014, doi:10.1016/j.encep.2014.06.005.