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A subtype of schizophrenia patients with altered methylation level of genes related to immune cell activity

Published online by Cambridge University Press:  20 March 2024

Chunyan Luo ,
Xuenan Pi ,
Qi Zhang ,
Na Hu ,
Yuan Xiao ,
John A. Sweeney ,
Jeffrey R. Bishop ,
Qiyong Gong ,
Dan Xie  and
Su Lui Open the ORCID record for Su Lui [Opens in a new window]
Chunyan Luo
Affiliation:
Huaxi MR Research Center (HMRRC), Department of Radiology, Functional and molecular imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China Psychoradiology Research Unit of the Chinese Academy of Medical Sciences (2018RU011), West China Hospital of Sichuan University, Chengdu, China
Xuenan Pi
Affiliation:
Laboratory of Omics Technology and Bioinformatics, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
Qi Zhang
Affiliation:
Huaxi MR Research Center (HMRRC), Department of Radiology, Functional and molecular imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China Psychoradiology Research Unit of the Chinese Academy of Medical Sciences (2018RU011), West China Hospital of Sichuan University, Chengdu, China
Na Hu
Affiliation:
Huaxi MR Research Center (HMRRC), Department of Radiology, Functional and molecular imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China Psychoradiology Research Unit of the Chinese Academy of Medical Sciences (2018RU011), West China Hospital of Sichuan University, Chengdu, China
Yuan Xiao
Affiliation:
Huaxi MR Research Center (HMRRC), Department of Radiology, Functional and molecular imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China Psychoradiology Research Unit of the Chinese Academy of Medical Sciences (2018RU011), West China Hospital of Sichuan University, Chengdu, China
John A. Sweeney
Affiliation:
Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati OH 45219, USA
Jeffrey R. Bishop
Affiliation:
Department of Experimental and Clinical Pharmacology and Department of Psychiatry, University of Minnesota, Minneapolis, MN, USA
Qiyong Gong
Affiliation:
Huaxi MR Research Center (HMRRC), Department of Radiology, Functional and molecular imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China Psychoradiology Research Unit of the Chinese Academy of Medical Sciences (2018RU011), West China Hospital of Sichuan University, Chengdu, China
Dan Xie*
Affiliation:
Laboratory of Omics Technology and Bioinformatics, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
Su Lui*
Affiliation:
Huaxi MR Research Center (HMRRC), Department of Radiology, Functional and molecular imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China Psychoradiology Research Unit of the Chinese Academy of Medical Sciences (2018RU011), West China Hospital of Sichuan University, Chengdu, China
*
Corresponding author: Dan Xie; Email: danxie@scu.edu.cn; Su Lui; Email: lusuwcums@hotmail.com
Corresponding author: Dan Xie; Email: danxie@scu.edu.cn; Su Lui; Email: lusuwcums@hotmail.com
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Abstract

Background

Epigenetic changes are plausible molecular sources of clinical heterogeneity in schizophrenia. A subgroup of schizophrenia patients with elevated inflammatory or immune-dysregulation has been reported by previous studies. However, little is known about epigenetic changes in genes related to immune activation in never-treated first-episode patients with schizophrenia (FES) and its consistency with that in treated long-term ill (LTS) patients.

Methods

In this study, epigenome-wide profiling with a DNA methylation array was applied using blood samples of both FES and LTS patients, as well as their corresponding healthy controls. Non-negative matrix factorization (NMF) and k -means clustering were performed to parse heterogeneity of schizophrenia, and the consistency of subtyping results from two cohorts. was tested.

Results

This study identified a subtype of patients in FES participants (47.5%) that exhibited widespread methylation level alterations of genes enriched in immune cell activity and a significantly higher proportion of neutrophils. This clustering of FES patients was validated in LTS patients, with high correspondence in epigenetic and clinical features across two cohorts

Conclusions

In summary, this study demonstrated a subtype of schizophrenia patients across both FES and LTS cohorts, defined by widespread alterations in methylation profile of genes related to immune function and distinguishing clinical features. This finding illustrates the promise of novel treatment strategies targeting immune dysregulation for a subpopulation of schizophrenia patients.

Keywords

DNA methylationfirst-episodeimmune dysfunctionschizophreniasubtype
Type
Original Article
Information
Psychological Medicine , Volume 54 , Issue 10 , July 2024 , pp. 2538 - 2546
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Copyright
Copyright © The Author(s), 2024. Published by Cambridge University Press

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Footnotes

*

Chunyan Luo and Xuenan Pi contribute equally to this work.

References

Aryee, M. J., Jaffe, A. E., Corrada-Bravo, H., Ladd-Acosta, C., Feinberg, A. P., Hansen, K. D., & Irizarry, R. A. (2014). Minfi: A flexible and comprehensive bioconductor package for the analysis of infinium DNA methylation microarrays. Bioinformatics (Oxford, England), 30(10), 1363–1369. https://doi.org/10.1093/bioinformatics/btu049Google ScholarPubMed
Benros, M. E., Eaton, W. W., & Mortensen, P. B. (2014). The epidemiologic evidence linking autoimmune diseases and psychosis. Biological psychiatry, 75(4), 300–306. https://doi.org/10.1016/j.biopsych.2013.09.023CrossRefGoogle ScholarPubMed
Bhikram, T., & Sandor, P. (2022). Neutrophil–lymphocyte ratios as inflammatory biomarkers in psychiatric patients. Brain, Behavior, and Immunity, 105, 237–246. https://doi.org/10.1016/j.bbi.2022.07.006CrossRefGoogle ScholarPubMed
Boerrigter, D., Weickert, T. W., Lenroot, R., O'Donnell, M., Galletly, C., Liu, D., … Weickert, C. S. (2017). Using blood cytokine measures to define high inflammatory biotype of schizophrenia and schizoaffective disorder. Journal of Neuroinflammation, 14(1), 188. https://doi.org/10.1186/s12974-017-0962-yCrossRefGoogle ScholarPubMed
Brunet, J. P., Tamayo, P., Golub, T. R., & Mesirov, J. P. (2004). Metagenes and molecular pattern discovery using matrix factorization. Proceedings of the National Academy of Sciences of the United States of America, 101(12), 4164–4169. https://doi.org/10.1073/pnas.0308531101CrossRefGoogle ScholarPubMed
Burghardt, K. J., Khoury, A. S., Msallaty, Z., Yi, Z., & Seyoum, B. (2020). Antipsychotic medications and DNA methylation in schizophrenia and bipolar disorder: A systematic review. Pharmacotherapy, 40(4), 331–342. https://doi.org/10.1002/phar.2375CrossRefGoogle ScholarPubMed
Cakici, N., van Beveren, N. J. M., Judge-Hundal, G., Koola, M. M., & Sommer, I. E. C. (2019). An update on the efficacy of anti-inflammatory agents for patients with schizophrenia: A meta-analysis. Psychological Medicine, 49(14), 2307–2319. https://doi.org/10.1017/S0033291719001995CrossRefGoogle ScholarPubMed
Clementz, B. A., Parker, D. A., Trotti, R. L., McDowell, J. E., Keedy, S. K., Keshavan, M. S., … Tamminga, C. A. (2022). Psychosis biotypes: Replication and validation from the B-SNIP consortium. Schizophrenia Bulletin, 48(1), 56–68. https://doi.org/10.1093/schbul/sbab090CrossRefGoogle ScholarPubMed
de Witte, L., Tomasik, J., Schwarz, E., Guest, P. C., Rahmoune, H., Kahn, R. S., & Bahn, S. (2014). Cytokine alterations in first-episode schizophrenia patients before and after antipsychotic treatment. Schizophrenia Research, 154(1–3), 23–29. https://doi.org/10.1016/j.schres.2014.02.005CrossRefGoogle ScholarPubMed
Fillman, S. G., Sinclair, D., Fung, S. J., Webster, M. J., & Shannon Weickert, C. (2014). Markers of inflammation and stress distinguish subsets of individuals with schizophrenia and bipolar disorder. Translational Psychiatry, 4(2), e365. https://doi.org/10.1038/tp.2014.8CrossRefGoogle Scholar
Fillman, S. G., Weickert, T. W., Lenroot, R. K., Catts, S. V., Bruggemann, J. M., Catts, V. S., & Weickert, C. S. (2016). Elevated peripheral cytokines characterize a subgroup of people with schizophrenia displaying poor verbal fluency and reduced Broca's area volume. Molecular Psychiatry, 21(8), 1090–1098. https://doi.org/10.1038/mp.2015.90CrossRefGoogle ScholarPubMed
First, M., Spitzer, R., Gibbon, M., & Williams, J. (1995). Structured clinical interview for DSM-IV axis I disorders, patient edition (SCID-I/P). New York: Biometrics Research, New York State Psychiatry Institute.Google Scholar
Fortin, J. P., Triche, T. J. Jr, & Hansen, K. D. (2017). Preprocessing, normalization and integration of the illumina human methylation EPIC array with minfi. Bioinformatics (Oxford, England), 33(4), 558–560. https://doi.org/10.1093/bioinformatics/btw691Google ScholarPubMed
Hoang, D., Xu, Y., Lutz, O., Bannai, D., Zeng, V., Bishop, J. R., … Lizano, P. (2022). Inflammatory subtypes in antipsychotic-naïve first-episode schizophrenia are associated with altered brain morphology and topological organization. Brain, Behavior, and Immunity, 100, 297–308. https://doi.org/10.1016/j.bbi.2021.11.019CrossRefGoogle ScholarPubMed
Houseman, E. A., Accomando, W. P., Koestler, D. C., Christensen, B. C., Marsit, C. J., Nelson, H. H., … Kelsey, K. T. (2012). DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinformatics, 13, 86. https://doi.org/10.1186/1471-2105-13-86CrossRefGoogle ScholarPubMed
Ivleva, E. I., Turkozer, H. B., & Sweeney, J. A. (2020). Imaging-based subtyping for psychiatric syndromes. Neuroimaging Clinics of North America, 30(1), 35–44. https://doi.org/10.1016/j.nic.2019.09.005CrossRefGoogle Scholar
Kay, S. R., Opler, L. A., & Lindenmayer, J. P. (1989). The Positive and Negative Syndrome Scale (PANSS): Rationale and standardisation. The British Journal of Psychiatry. Supplement, (7), 59–67. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/2619982CrossRefGoogle ScholarPubMed
Keefe, R. S., Goldberg, T. E., Harvey, P. D., Gold, J. M., Poe, M. P., & Coughenour, L. (2004). The brief assessment of cognition in schizophrenia: Reliability, sensitivity, and comparison with a standard neurocognitive battery. Schizophrenia Research, 68(2–3), 283–297. https://doi.org/10.1016/j.schres.2003.09.011CrossRefGoogle ScholarPubMed
Leek, J. T., Johnson, W. E., Parker, H. S., Jaffe, A. E., & Storey, J. D. (2012). The sva package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics (Oxford, England), 28(6), 882–883. https://doi.org/10.1093/bioinformatics/bts034Google Scholar
Lizano, P., Lutz, O., Xu, Y., Rubin, L. H., Paskowitz, L., Lee, A. M., … Bishop, J. R. (2021). Multivariate relationships between peripheral inflammatory marker subtypes and cognitive and brain structural measures in psychosis. Molecular Psychiatry, 26(7), 3430–3443. https://doi.org/10.1038/s41380-020-00914-0CrossRefGoogle ScholarPubMed
Luo, C., Pi, X., Hu, N., Wang, X., Xiao, Y., Li, S., … Lui, S. (2021). Subtypes of schizophrenia identified by multi-omic measures associated with dysregulated immune function. Molecular Psychiatry, 26(11), 6926–6936. https://doi.org/10.1038/s41380-021-01308-6CrossRefGoogle ScholarPubMed
Miller, B. J., & Goldsmith, D. R. (2017). Towards an immunophenotype of schizophrenia: Progress, potential mechanisms, and future directions. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology, 42(1), 299–317. https://doi.org/10.1038/npp.2016.211CrossRefGoogle ScholarPubMed
Moody, G., & Miller, B. J. (2018). Total and differential white blood cell counts and hemodynamic parameters in first-episode psychosis. Psychiatry Research, 260, 307–312. https://doi.org/10.1016/j.psychres.2017.11.086CrossRefGoogle ScholarPubMed
Pape, K., Tamouza, R., Leboyer, M., & Zipp, F. (2019). Immunoneuropsychiatry – novel perspectives on brain disorders. Nature reviews. Neurology, 15(6), 317–328. https://doi.org/10.1038/s41582-019-0174-4CrossRefGoogle ScholarPubMed
Pasternak, O., Westin, C. F., Bouix, S., Seidman, L. J., Goldstein, J. M., Woo, T. U., … Kubicki, M. (2012). Excessive extracellular volume reveals a neurodegenerative pattern in schizophrenia onset. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 32(48), 17365–17372. https://doi.org/10.1523/JNEUROSCI.2904-12.2012CrossRefGoogle ScholarPubMed
Pillinger, T., Osimo, E. F., Brugger, S., Mondelli, V., McCutcheon, R. A., & Howes, O. D. (2019). A meta-analysis of immune parameters, variability, and assessment of modal distribution in psychosis and test of the immune subgroup hypothesis. Schizophrenia Bulletin, 45(5), 1120–1133. https://doi.org/10.1093/schbul/sby160CrossRefGoogle ScholarPubMed
Prestwood, T. R., Asgariroozbehani, R., Wu, S., Agarwal, S. M., Logan, R. W., Ballon, J. S., … Freyberg, Z. (2021). Roles of inflammation in intrinsic pathophysiology and antipsychotic drug-induced metabolic disturbances of schizophrenia. Behavioural Brain Research, 402, 113101. https://doi.org/10.1016/j.bbr.2020.113101CrossRefGoogle Scholar
Rahmani, E., Yedidim, R., Shenhav, L., Schweiger, R., Weissbrod, O., Zaitlen, N., & Halperin, E. (2017). GLINT: A user-friendly toolset for the analysis of high-throughput DNA-methylation array data. Bioinformatics (Oxford, England), 33(12), 1870–1872. https://doi.org/10.1093/bioinformatics/btx059Google Scholar
Reinius, L. E., Acevedo, N., Joerink, M., Pershagen, G., Dahlen, S. E., Greco, D., … Kere, J. (2012). Differential DNA methylation in purified human blood cells: Implications for cell lineage and studies on disease susceptibility. PLoS One, 7(7), e41361. https://doi.org/10.1371/journal.pone.0041361CrossRefGoogle ScholarPubMed
Saha, S., Chant, D., & McGrath, J. (2007). A systematic review of mortality in schizophrenia: Is the differential mortality gap worsening over time? Archives of General Psychiatry, 64(10), 1123–1131. https://doi.org/10.1001/archpsyc.64.10.1123CrossRefGoogle ScholarPubMed
Schizophrenia Working Group of the Psychiatric Genomics, C (2014). Biological insights from 108 schizophrenia-associated genetic loci. Nature, 511(7510), 421–427. https://doi.org/10.1038/nature13595CrossRefGoogle Scholar
Schwarzer, G. (2007). meta: An R package for meta-analysis.CrossRefGoogle Scholar
Singh, S. P., Cooper, J. E., Fisher, H. L., Tarrant, C. J., Lloyd, T., Banjo, J., … Jones, P. (2005). Determining the chronology and components of psychosis onset: The Nottingham Onset Schedule (NOS). Schizophrenia Research, 80(1), 117–130. https://doi.org/10.1016/j.schres.2005.04.018CrossRefGoogle ScholarPubMed
Smigielski, L., Jagannath, V., Rössler, W., Walitza, S., & Grünblatt, E. (2020). Epigenetic mechanisms in schizophrenia and other psychotic disorders: A systematic review of empirical human findings. Molecular Psychiatry, 25(8), 1718–1748. https://doi.org/10.1038/s41380-019-0601-3CrossRefGoogle ScholarPubMed
Steiner, J., Frodl, T., Schiltz, K., Dobrowolny, H., Jacobs, R., Fernandes, B. S., … Bernstein, H. G. (2020). Innate immune cells and C-reactive protein in acute first-episode psychosis and schizophrenia: Relationship to psychopathology and treatment. Schizophrenia Bulletin, 46(2), 363–373. https://doi.org/10.1093/schbul/sbz068Google Scholar
Teschendorff, A. E., Marabita, F., Lechner, M., Bartlett, T., Tegner, J., Gomez-Cabrero, D., & Beck, S. (2013). A beta-mixture quantile normalization method for correcting probe design bias in Illumina Infinium 450 k DNA methylation data. Bioinformatics (Oxford, England), 29(2), 189–196. https://doi.org/10.1093/bioinformatics/bts680Google ScholarPubMed
Teschendorff, A. E., Menon, U., Gentry-Maharaj, A., Ramus, S. J., Gayther, S. A., Apostolidou, S., … Widschwendter, M. (2009). An epigenetic signature in peripheral blood predicts active ovarian cancer. PLoS One, 4(12), e8274. https://doi.org/10.1371/journal.pone.0008274CrossRefGoogle ScholarPubMed
Tian, Y., Morris, T. J., Webster, A. P., Yang, Z., Beck, S., Feber, A., & Teschendorff, A. E. (2017). ChAMP: Updated methylation analysis pipeline for Illumina BeadChips. Bioinformatics (Oxford, England), 33(24), 3982–3984. https://doi.org/10.1093/bioinformatics/btx513Google ScholarPubMed
Velthorst, E., Fett, A. J., Reichenberg, A., Perlman, G., van Os, J., Bromet, E. J., & Kotov, R. (2017). The 20-year longitudinal trajectories of social functioning in individuals with psychotic disorders. The American Journal of Psychiatry, 174(11), 1075–1085. https://doi.org/10.1176/appi.ajp.2016.15111419CrossRefGoogle ScholarPubMed
Xiao, Y., Liao, W., Long, Z., Tao, B., Zhao, Q., Luo, C., … Gong, Q. (2022). Subtyping schizophrenia patients based on patterns of structural brain alterations. Subtyping schizophrenia patients based on patterns of structural brain alterations. Schizophrenia Bulletin, 48(1), 241–250. https://doi.org/10.1093/schbul/sbab110CrossRefGoogle ScholarPubMed
Xiao, Y., Sun, H., Shi, S., Jiang, D., Tao, B., Zhao, Y., … Lui, S. (2018). White matter abnormalities in never-treated patients with long-term schizophrenia. The American Journal of Psychiatry, 175(11), 1129–1136. https://doi.org/10.1176/appi.ajp.2018.17121402CrossRefGoogle ScholarPubMed
Yu, G., Wang, L. G., Han, Y., & He, Q. Y. (2012). clusterProfiler: An R package for comparing biological themes among gene clusters. Omics: A Journal of Integrative Biology, 16(5), 284–287. https://doi.org/10.1089/omi.2011.0118CrossRefGoogle Scholar
Zhang, W., Deng, W., Yao, L., Xiao, Y., Li, F., Liu, J., … Gong, Q. (2015). Brain structural abnormalities in a group of never-medicated patients with long-term schizophrenia. The American Journal of Psychiatry, 172(10), 995–1003. https://doi.org/10.1176/appi.ajp.2015.14091108CrossRefGoogle Scholar
Zhang, W., Sweeney, J. A., Bishop, J. R., Gong, Q., & Lui, S. (2023). Biological subtyping of psychiatric syndromes as a pathway for advances in drug discovery and personalized medicine. Nature Mental Health, 1(2), 88–99. https://doi.org/10.1038/s44220-023-00019-xCrossRefGoogle Scholar
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