Skip to main content

Advertisement

SpringerLink
Log in

DNA Methylation Signatures of Peripheral Leukocytes in Schizophrenia

  • Original Paper
  • Published:
NeuroMolecular Medicine Aims and scope Submit manuscript

Abstract

Schizophrenia (SCZ) is a complex psychiatric disease with a lifetime morbidity rate of 0.5–1.0 %. To date, aberrant DNA methylation in SCZ has been reported in several studies. However, no comprehensive studies using medication-free subjects with SCZ have been conducted. In addition, most of these studies have been limited to the analysis of the CpG sites in CpG islands (CGIs) in the gene promoter regions, so little is known about the DNA methylation signatures across the whole genome in SCZ. Genome-wide DNA methylation profiling (485,764 CpG sites) of peripheral leukocytes was conducted in the first set of samples (24 medication-free patients with SCZ and 23 non-psychiatric controls) using Infinium HumanMethylation450 Beadchips. Second, a monozygotic twin study was performed using three pairs of monozygotic twins that were discordant for SCZ. Finally, the data from these two independent cohorts were compared. A total of 234 differentially methylated CpG sites that were common between these two cohorts were identified. Of the 234 CpG sites, 153 sites (65.4 %) were located in the CGIs and in the regions flanking CGIs (CGI: 40.6 %; CGI shore: 13.3 %; CGI shelf: 11.5 %). Of the 95 differently methylated CpG sites in the CGIs, most of them were located in the promoter regions (promoter: 75.8 %; gene body: 14.7 %; 3′-UTR: 2.1 %). Aberrant DNA methylation in SCZ was identified at numerous loci across the whole genome in peripheral leukocytes using two independent sets of samples. These findings support the notion that altered DNA methylation could be involved in the pathophysiology of SCZ.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Abdolmaleky, H. M., Cheng, K. H., Faraone, S. V., Wilcox, M., Glatt, S. J., Gao, F., et al. (2006). Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder. Human Molecular Genetics, 15, 3132–3145.

    Article  PubMed  CAS  Google Scholar 

  • Ball, M. P., Li, J. B., Gao, Y., Lee, J., LeProust, E. M., Park, I., et al. (2009). Targeted and genome-scale strategies reveal gene-body methylation signatures in human cells. Nature Biotechnology, 27, 361–368.

    Article  PubMed  CAS  Google Scholar 

  • Bhugra, D. (2005). The global prevalence of schizophrenia. PLoS Medicine, 2, e151–e175.

    Article  PubMed  Google Scholar 

  • Bhutani, N., Burns, D. M., & Blau, H. M. (2011). DNA demethylation dynamics. Cell, 146, 866–872.

    Article  PubMed  CAS  Google Scholar 

  • Bibikova, M., Barnes, B., Tsan, C., Ho, V., Klotzle, B., Le, J. M., et al. (2011). High density DNA methylation array with single CpG site resolution. Genomics, 98, 288–295.

    Article  PubMed  CAS  Google Scholar 

  • Cardno, A. G., & Gottesman, I. I. (2000). Twin studies of schizophrenia: From bow-and-arrowconcordances to star wars Mx and functional genomics. American Journal of Medical Genetics, 97, 12–17.

    Article  PubMed  CAS  Google Scholar 

  • Carrard, A., Salzmann, A., Malafosse, A., & Karege, F. (2011). Increased DNA methylation status of the serotonin receptor 5HTR1A gene promoter in schizophrenia and bipolar disorder. Journal of Affective Disorders, 132, 450–453.

    Article  PubMed  CAS  Google Scholar 

  • Chen, Y., Zhang, J., Zhang, L., Shen, Y., Xu, Q. (2011). Effects of MAOA promoter methylation on susceptibility to paranoid schizophrenia. Human Genetics [Epub ahead of print].

  • Colantuoni, C., Lipska, B. K., Ye, T., Hyde, T. M., Tao, R., Leek, J. T., et al. (2011). Temporal dynamics and genetic control of transcription in the human prefrontal cortex. Nature, 478, 519–523.

    Article  PubMed  CAS  Google Scholar 

  • Datta, S. R., McQuillin, A., Rizig, M., Blaveri, E., Thirumalai, S., Kalsi, G., et al. (2010). A threonine to isoleucine missense mutation in the pericentriolar material 1 gene is strongly associated with schizophrenia. Molecular Psychiatry, 15, 615–628.

    Article  PubMed  CAS  Google Scholar 

  • Deaton, A. M., Webb, S., Kerr, A. R. W., Illingworth, R. S., Guy, J., Andrews, R., et al. (2011). Cell type-specific DNA methylation at intragenic CpG islands in the immune system. Genome Research, 21, 1074–1086.

    Article  PubMed  CAS  Google Scholar 

  • Dedeurwaerder, S., Defrance, M., Calonne, E., & Sotiriou, C. (2011). Evaluation of the Infinium 450 K technology. Epigenomics, 3, 771–784.

    Article  PubMed  CAS  Google Scholar 

  • Dempster, E. L., Pidsley, R., Schalkwyk, L. C., Owens, S., Georgiades, A., Kane, F., et al. (2011). Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder. Human Molecular Genetics, 20, 4786–4796.

    Article  PubMed  CAS  Google Scholar 

  • Dong, E., Nelson, M., Grayson, D. R., Costa, E., & Guidotti, A. (2008). Clozapine and sulpiride but not haloperidol or olanzapine activate brain DNA demethylation. Proceedings of National Academy of Sciences of the United States of America, 105, 13614–13619.

    Article  CAS  Google Scholar 

  • Gervin, K., Vigeland, M. D., Mattingsdal, M., Hammerø, M., Nygård, H., Olsen, A. O., et al. (2012). DNA methylation and gene expression changes in monozygotic twins discordant for psoriasis: Identification of epigenetically dysregulated genes. PLoS Genetics, 8, e1002454.

    Article  PubMed  CAS  Google Scholar 

  • Grayson, D. R., Jia, X., Chen, Y., Sharma, R. P., Mitchell, C. P., Guidotti, A., et al. (2005). Reelin promoter hypermethylation in schizophrenia. Proceedings of National Academy of Sciences of the United States of America, 10, 9341–9346.

    Article  Google Scholar 

  • Gurling, H. M., Critchley, H., Datta, S. R., McQuillin, A., Blaveri, E., Thirumalai, S., et al. (2006). Genetic association and brain morphology studies and the chromosome 8p22 pericentriolar material 1 (PCM1) gene in susceptibility to schizophrenia. Archives of General Psychiatry, 63, 844–854.

    Article  PubMed  Google Scholar 

  • Harrison, P. J., & Weinberger, D. R. (2005). Schizophrenia genes, gene expression, and neuropathology: On the matter of their convergence. Molecular Psychiatry, 10, 40–68.

    Article  PubMed  CAS  Google Scholar 

  • Illingworth, R. S., Gruenewald-Schneider, U., Webb, S., Kerr, A. R., James, K. D., Turner, D. J., et al. (2010). Orphan CpG islands identify numerous conserved promoters in the mammalian genome. PLoS Genetics, 6, e1001134.

    Article  PubMed  Google Scholar 

  • International Schizophrenia Consortium. (2008). Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature, 455, 237–241.

    Article  Google Scholar 

  • Irizarry, R. A., Ladd-Acosta, C., Wen, B., Wu, Z., Montano, C., Onyango, P., et al. (2009). The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nature Genetics, 41, 178–186.

    Article  PubMed  CAS  Google Scholar 

  • Iwamoto, K., Bundo, M., Yamada, K., Takao, H., Iwayama-Shigeno, Y., Yoshikawa, T., et al. (2005). DNA methylation status of SOX10 correlates with its downregulation and oligodendrocyte dysfunction in schizophrenia. The Journal of Neuroscience, 25, 5376–5381.

    Article  PubMed  CAS  Google Scholar 

  • Javierre, B. M., Fernandez, A. F., Richter, J., Al-Shahrour, F., Martin-Subero, J. I., Rodriguez-Ubreva, J., et al. (2010). Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. Genome Research, 20, 170–179.

    Article  PubMed  CAS  Google Scholar 

  • Kähler, A. K., Djurovic, S., Rimol, L. M., Brown, A. A., Athanasiu, L., Jönsson, E. G., et al. (2011). Candidate gene analysis of the human natural killer-1 carbohydrate pathway and perineuronal nets in schizophrenia: B3GAT2 is associated with disease risk and cortical surface area. Biological Psychiatry, 69, 90–96.

    Article  PubMed  Google Scholar 

  • Kaminsky, Z., Tochigi, M., Jia, P., Pal, M., Mill, J., Kwan, A., et al. (2012). A multi-tissue analysis identifies HLA complex group 9 gene methylation differences in bipolar disorder. Molecular Psychiatry, 17(7), 728–740.

    Google Scholar 

  • Kim, T., Park, J. K., Kim, H. J., Chung, J. H., & Kim, J. W. (2010). Association of histone deacetylase genes with schizophrenia in Korean population. Psychiatry Research, 178, 266–269.

    Article  PubMed  CAS  Google Scholar 

  • Kuratomi, G., Iwamoto, K., Bundo, M., Kusumi, I., Kato, N., Iwata, N., et al. (2008). Aberrant DNA methylation associated with bipolar disorder identified from discordant monozygotic twins. Molecular Psychiatry, 13, 429–441.

    Article  PubMed  CAS  Google Scholar 

  • Lavedan, C., Licamele, L., Volpi, S., Hamilton, J., Heaton, C., Mack, K., et al. (2009). Association of the NPAS3 gene and five other loci with response to the antipsychotic iloperidone identified in a whole genome association study. Molecular Psychiatry, 14, 804–819.

    Article  PubMed  CAS  Google Scholar 

  • Leek, J. T., & Storey, J. D. (2007). Capturing heterogeneity in gene expression studies by surrogate variable analysis. PLoS Genetics, 3, 1724–1735.

    Article  PubMed  CAS  Google Scholar 

  • Lett, T. A., Wallance, T. J. M., Chowdhur, N. I., Tiwari, A. K., Kennedy, J. L., & Muller, D. J. (2011). Pharmacogenetics of antipsychotic-induced weight gain: Review and clinical implications. Molecular Psychiatry, 17, 242–266.

    Article  PubMed  Google Scholar 

  • Maunakea, A. K., Nagarajan, R. P., Bilenky, M., Ballinger, T. J., D’souza, C., Fouse, S. D., et al. (2010). Conserved role of intragenic DNA mehtylaion in regulating alternative promoters. Nature, 466, 253–257.

    Article  PubMed  CAS  Google Scholar 

  • Melas, P. A., Rogdaki, M., Osby, U., Challing, M., Lavebratt, C., & Ekstrom, T. J. (2012). Epigenetic aberrations in leukocytes of patients with schizophrenia: Association of global DNA methylation with antipsychotic drug treatment and disease onset. The FASEB Journal, 26, 2712–2718.

    Article  CAS  Google Scholar 

  • Mill, J., Tang, T., Kaminsky, Z., Khare, T., Yazdanpanah, S., Bouchard, L., et al. (2008). Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. American Journal of Human Genetics, 82, 696–711.

    Article  PubMed  CAS  Google Scholar 

  • Moskvina, V., Craddock, P., Nikolov, I., Pahwa, J. S., Green, E., Wellcome Trust Case Control Consortium, et al. (2009). Gene-wide analysis of genome-wide association data sets: Evidence for multiple common risk alleles for schizophrenia and bipolar disorder and for overlap in genetic risk. Molecular Psychiatry, 14, 252–260.

    Article  PubMed  CAS  Google Scholar 

  • Nohesara, S., Ghadirivasfi, M., Mostafavi, S., Eskandari, M. R., Ahmadkhaniha, H., Thiagalingam, S., et al. (2011). DNA hypomethylation of MB-COMT promoter in the DNA derived from saliva in schizophrenia and bipolar disorder. Journal of Psychiatic Research, 45, 1432–1438.

    Article  Google Scholar 

  • Numata, S., Ye, T., Hyde, T. M., Guitart-Navarro, X., Tao, R., Wininger, M., et al. (2012). DNA methylation signatures in development and aging of the human prefrontal cortex. American Journal of Human Genetics, 90, 260–272.

    Article  PubMed  CAS  Google Scholar 

  • Ono, S., Imamura, A., Tasaki, S., Kurotaki, N., Ozawa, H., Yoshiura, K., et al. (2010). Failure to confirm CNVs as of aetiological significance in twin pairs discordant for schizophrenia. Twin Research and Human Genetics, 13, 455–460.

    Article  PubMed  Google Scholar 

  • Petronis, A., Gottesman, I. I., Crow, T. J., DeLisi, L. E., Klar, A. J., Macciardi, F., et al. (2000). Psychiatric epigenetics: A new focus for the new century. Molecular Psychiatry, 5, 34234–34236.

    Google Scholar 

  • Purcell, S. M., Wray, N. R., Stone, J. L., Visscher, P. M., O’Donovan, M. C., Sullivan, P. F., et al. (2009). Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature, 460, 748–752.

    PubMed  CAS  Google Scholar 

  • Rakyan, V. K., Beyan, H., Down, T., Hawa, M. I., Maslau, S., Aden, D., et al. (2011). Identification of type 1 diabetes–associated DNA methylation variable positions that precede disease diagnosis. PLoS Genetics, 7, e1002300.

    Article  PubMed  CAS  Google Scholar 

  • Rees, E., Moskvina, V., Owen, M. J., O’Donovan, M. C., & Kirov, G. (2011). De novo rates and selection of schizophrenia-associated copy number variations. Biological Psychiatry, 70, 1109–1114.

    Article  PubMed  Google Scholar 

  • Sandoval, J., Heyn, H., Moran, S., Serra-Musach, J., Pujana, M. A., Bibikova, M., et al. (2011). Validation of a DNA methylation microarray for 450,000 CpG sites in the human genome. Epigenetics, 6, 692–702.

    Article  PubMed  CAS  Google Scholar 

  • Shann, Y. J., Cheng, C., Chiao, C. H., Chen, D. T., Li, P. H., & Hsu, M. T. (2008). Genome-wide mapping and characterization of hypomethylated sites in human tissues and breast cancer cell lines. Genome Research, 18, 791–801.

    Article  PubMed  CAS  Google Scholar 

  • Shi, J., Levinson, D. F., Duan, J., Sanders, A. R., Zheng, Y., Pe’er, I., et al. (2009). Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature, 460, 753–757.

    PubMed  CAS  Google Scholar 

  • Shimabukuro, M., Jinno, Y., Fuke, C., & Okazaki, Y. (2006). Haloperidol treatment induces tissue- and sex-specific changes in DHA methylation: A control study using rats. Behavioral and Brain Functions, 2, 37.

    Article  PubMed  Google Scholar 

  • Siegmund, K. D., Connor, C. M., Campan, M., Long, T. I., Weisenberger, D. J., Biniszkiewicz, D., et al. (2007). DNA methylation in the human cerebral cortex is dynamically regulated throughout the life span and involves differentiated neurons. PLoS ONE, 2(9), e895.

    Article  PubMed  Google Scholar 

  • Souza, R. P., de Luca, V., Remington, G., Lieberman, J. A., Meltzer, H. Y., Kennedy, J. L., et al. (2010a). Glial cell line-derived neurotrophic factor alpha 2 (GFRA2) gene is associated with tardive dyskinesia. Psychopharmacology (Berl), 210, 347–354.

    Article  CAS  Google Scholar 

  • Souza, R. P., Romano-Silva, M. A., Lieberman, J. A., Meltzer, H. Y., MacNeil, L. T., Culotti, J. G., et al. (2010b). Genetic association of the GDNF alpha-receptor genes with schizophrenia and clozapine response. Journal of Psychiatry Research, 44, 700–706.

    Article  Google Scholar 

  • Stefansson, H., Ophoff, R. A., Steinberg, S., Andreassen, O. A., Cichon, S., Rujescu, D., et al. (2009). Common variants conferring risk of schizophrenia. Nature, 460, 744–747.

    PubMed  CAS  Google Scholar 

  • Sullivan, P. F., Kendler, K. S., & Neale, M. C. (2003). Schizophrenia as a complex trait: Evidence from a meta-analysis of twin studies. Archives of General Psychiatry, 60, 1187–1192.

    Article  PubMed  Google Scholar 

  • Tremolizzo, L., Doueiri, M. S., Dong, E., Grayson, D. R., Davis, J., Pinna, G., et al. (2005). Valproate corrects the schizophrenia-like epigenetic behavioral modifications induced by methionine in mice. Biological Psychiatry, 57, 500–550.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to thank all the volunteers who understood our study purpose and participated in this study, and the physicians who helped us to collect clinical data and blood samples at the mental hospitals. The authors would also like to thank Mrs. Akemi Okada for her technical assistance. This work was supported by Japan Science and Technology Agency, CREST and by a Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology. The all authors report no biomedical financial interests or potential conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Psychiatry, Course of Integrated Brain Sciences, Medical Informatics, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-8-15 Kuramoto-cho, Tokushima, 770-8503, Japan

    Makoto Kinoshita, Shusuke Numata, Jun-ichi Iga, Shinya Watanabe, Kumiko Kikuchi, Hiroko Kubo, Masahito Nakataki, Satsuki Sumitani & Tetsuro Ohmori

  2. Department of Human Genetics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan

    Atsushi Tajima & Issei Imoto

  3. Department of Neuropsychiatry, Kochi Medical School, Kochi, Japan

    Shinji Shimodera

  4. Department of Neuropsychiatry, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan

    Shinji Ono & Akira Imamura

  5. Tokyo Metropolitan Matsuzawa Hospital, Tokyo, Japan

    Yuji Okazaki

Authors
  1. Makoto Kinoshita
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shusuke Numata
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Atsushi Tajima
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shinji Shimodera
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shinji Ono
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Akira Imamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jun-ichi Iga
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shinya Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kumiko Kikuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hiroko Kubo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Masahito Nakataki
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Satsuki Sumitani
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Issei Imoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yuji Okazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Tetsuro Ohmori
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shusuke Numata.

Additional information

Makoto Kinoshita and Shusuke Numata contributed equally to this work.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kinoshita, M., Numata, S., Tajima, A. et al. DNA Methylation Signatures of Peripheral Leukocytes in Schizophrenia. Neuromol Med 15, 95–101 (2013). https://doi.org/10.1007/s12017-012-8198-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12017-012-8198-6

Keywords

Search

Navigation