Multi-Epigenetic Landscapes of Schizophrenia: Epigenetic Landscapes of Schizophrenia

Sarmad Basit Saeed; Samia Afzal; Muhammad Shahid; Samreen Sarmad

doi:10.54393/pjhs.v6i7.3257

Authors

Sarmad Basit Saeed Centre of Excellence in Molecular Biology, University of Punjab, Lahore, Pakistan
Samia Afzal Centre of Excellence in Molecular Biology, University of Punjab, Lahore, Pakistan
Muhammad Shahid Centre of Excellence in Molecular Biology, University of Punjab, Lahore, Pakistan
Samreen Sarmad Forman Christian College, Kauser Abdullah Malik School of Life Sciences, Lahore, Pakistan

DOI:

https://doi.org/10.54393/pjhs.v6i7.3257

Keywords:

Schizophrenia, Epigenetics, DNA Methylation, Gene–Environment Interaction, Chromatin Remodeling, Psychiatric Epigenomics

Abstract

Schizophrenia is a debilitating neurodevelopmental disorder affecting approximately 1% of the global population. Traditional genetic models have provided limited insight into its complex etiology. This review synthesizes recent advances in epigenetic research related to schizophrenia, focusing on dynamic and reversible genome modifications. The study analyzed multi-omics and epigenomic profiling studies published between 2020 and 2025 that explore DNA methylation, histone modifications, non-coding RNAs and gene–environment interactions in schizophrenia. Epigenetic mechanisms, including DNA methylation, chromatin remodeling and non-coding RNAs, mediate environmental influences during critical neurodevelopmental periods, contributing to long-term gene expression changes associated with schizophrenia. These findings integrate genetic liability with environmental exposures and highlight potential biomarkers and therapeutic targets. Understanding schizophrenia through the lens of epigenetics may inform novel diagnostic and treatment approaches, advancing precision psychiatry.

References

Ghanbarzehi A, Sepehrinezhad A, Hashemi N, Karimi M, Shahbazi A. Disclosing Common Biological Signatures and Predicting New Therapeutic Targets in Schizophrenia and Obsessive–Compulsive Disorder by Integrated Bioinformatics Analysis. BioMed Central Psychiatry. 2023 Jan; 23(1): 40. doi: 10.1186/s12888-023-04543-z.

Andreassen OA, Hindley GF, Frei O, Smeland OB. New Insights from the Last Decade of Research in Psychiatric Genetics: Discoveries, Challenges and Clinical Implications. World Psychiatry. 2023 Feb; 22(1): 4-24. doi: 10.1002/wps.21034.

Wahbeh MH and Avramopoulos D. Gene-Environment Interactions in Schizophrenia: A Literature Review. Genes. 2021 Nov; 12(12): 1850. doi: 10.3390/genes12121850.

Hyman SL, Levy SE, Myers SM, Kuo DZ, Apkon S, Davidson LF et al. Identification, Evaluation, and Management of Children with Autism Spectrum Disorder. Pediatrics. 2020 Jan; 145(1). doi: 10.1542/9781610024716-part01-ch002.

Giordano GM, Brando F, Pezzella P, De Angelis M, Mucci A, Galderisi S. Factors Influencing the Outcome of Integrated Therapy Approach in Schizophrenia: A Narrative Review of the Literature. Frontiers in Psychiatry. 2022 Aug; 13: 970210. doi: 10.3389/fpsyt.2022.970210.

Legge SE, Pardiñas AF, O’Donovan MC. Genetics of Schizophrenia. Charney and Nestler’s Neurobiology of Mental Illness; Oxford University Press: Oxford, UK. 2025: 147. doi: 10.1093/med/9780197640654.003.0012.

Xu C, Fu X, Qin H, Yao K. Traversing the Epigenetic Landscape: DNA Methylation from Retina to Brain in Development and Disease. Frontiers in Cellular Neuroscience. 2024 Nov; 18: 1499719. doi: 10.3389/fncel.2024.1499719.

Shvedunova M and Akhtar A. Modulation of Cellular Processes by Histone and Non-Histone Protein Acetylation. Nature Reviews Molecular Cell Biology. 2022 May; 23(5): 329-49. doi: 10.1038/s41580-021-00441-y.

Martínez-Peula O, Morentin B, Callado LF, Meana JJ, Rivero G, Ramos-Miguel A. Permissive Epigenetic Regulatory Mechanisms at the Histone Level Are Enhanced in Postmortem Dorsolateral Prefrontal Cortex of Individuals with Schizophrenia. Journal of Psychiatry and Neuroscience. 2024 Feb; 49(1): E35-44. doi: 10.1503/jpn.230054.

Gandal MJ, Haney JR, Parikshak NN, Leppa V, Ramaswami G, Hartl C et al. Shared Molecular Neuropathology Across Major Psychiatric Disorders Parallels Polygenic Overlap. Science. 2018 Feb; 359(6376): 693-7. doi: 10.1126/science.aad6469.

Costa HE and Cairrao E. Effect of Bisphenol a on the Neurological System: A Review Update. Archives of Toxicology. 2024 Jan; 98(1): 1-73. doi: 10.1007/s00204-023-03614-0.

Cavalli G and Heard E. Advances in Epigenetics Link Genetics to the Environment and Disease. Nature. 2019 Jul; 571(7766): 489-99. doi: 10.1038/s41586-019-1411-0.

Fišar Z. Biological Hypotheses, Risk Factors, and Biomarkers of Schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2023 Jan; 120: 110626. doi: 10.1016/j.pnpbp.2022.110626.

Farrelly LA, Zheng S, Schrode N, Topol A, Bhanu NV, Bastle RM et al. Chromatin Profiling in Human Neurons Reveals Aberrant Roles for Histone Acetylation and BET Family Proteins in Schizophrenia. Nature Communications. 2022 Apr; 13(1): 2195. doi: 10.1038/s41467-022-29922-0.

Jin Y, Su K, Kong HE, Ma W, Wang Z, Li Y et al. Cell Type-Specific DNA Methylome Signatures Reveal Epigenetic Mechanisms for Neuronal Diversity and Neurodevelopmental Disorder. Human Molecular Genetics. 2023 Jan; 32(2): 218-30. doi: 10.1093/hmg/ddac189.

Hannon E, Dempster E, Viana J, Burrage J, Smith AR, Macdonald R et al. An Integrated Genetic-Epigenetic Analysis of Schizophrenia: Evidence for Co-Localization of Genetic Associations and Differential DNA Methylation. Genome Biology. 2016 Aug; 17(1): 176. doi: 10.1186/s13059-016-1041-x.

Di Carlo P, Punzi G, Ursini G. Brain-Derived Neurotrophic Factor and Schizophrenia. Psychiatric Genetics. 2019 Oct; 29(5): 200-10. doi: 10.1097/YPG.0000000000000237.

Cao DF, Zhou XY, Guo Q, Xiang MY, Bao MH, He BS et al. Unveiling the Role of Histone Deacetylases in Neurological Diseases: Focus on Epilepsy. Biomarker Research. 2024 Nov; 12(1): 142. doi: 10.1186/s40364-024-00687-6.

Ungar M. Multisystemic Resilience: Adaptation and Transformation in Contexts of Change. Oxford University Press. 2021. doi: 10.1093/oso/9780190095888.001.0001.

Pei JC, Luo DZ, Gau SS, Chang CY, Lai WS. Directly and Indirectly Targeting the Glycine Modulatory Site to Modulate NMDA Receptor Function to Address Unmet Medical Needs of Patients with schizophrenia. Frontiers in Psychiatry. 2021 Oct; 12: 742058. doi: 10.3389/fpsyt.2021.742058.

Kular L and Kular S. Epigenetics Applied to Psychiatry: Clinical Opportunities and Future Challenges. Psychiatry and Clinical Neurosciences. 2018 Apr; 72(4): 195-211. doi: 10.1111/pcn.12634

Zhou J, Fangma Y, Chen Z, Zheng Y. Post-stroke Neuropsychiatric Complications: Types, Pathogenesis, and Therapeutic Intervention. Aging and Disease. 2023 Dec; 14(6): 2127. doi: 10.14336/AD.2023.0310-2.

Andalman AS, Burns VM, Lovett-Barron M, Broxton M, Poole B, Yang SJ, Grosenick L, Lerner TN, Chen R, Benster T, Mourrain P. Neuronal dynamics regulating brain and behavioral state transitions. Cell. 2019 May 2;177(4):970-85. doi: 10.1016/j.cell.2019.02.037.

Girdhar K, Hoffman GE, Jiang Y, Brown L, Kundakovic M, Hauberg ME et al. Cell-Specific Histone Modification Maps in the Human Frontal Lobe Link Schizophrenia Risk to the Neuronal Epigenome. Nature Neuroscience. 2018 Aug; 21(8): 1126-36. doi: 10.1038/s41593-018-0187-0.

Turecki G and Meaney MJ. Effects of the Social Environment and Stress on Glucocorticoid Receptor Gene Methylation: A Systematic Review. Biological Psychiatry. 2016 Jan; 79(2): 87-96. doi: 10.1016/j.biopsych.2014.11.022.

Zhang TY, Labonté B, Wen XL, Turecki G, Meaney MJ. Epigenetic Mechanisms for the Early Environmental Regulation of Hippocampal Glucocorticoid Receptor Gene Expression in Rodents and Humans. Neuro-psychopharmacology. 2013 Jan; 38(1): 111-23. doi: 10.1038/npp.2012.149.

Szyf M. Epigenetics, A Key for Unlocking Complex CNS Disorders? Therapeutic Implications. European Neuro-psychopharmacology. 2015 May; 25(5): 682-702. doi: 10.1016/j.euroneuro.2014.01.009.

Zovkic IB, Meadows JP, Kaas GA, Sweatt JD. Interindividual Variability in Stress Susceptibility: A Role for Epigenetic Mechanisms in PTSD. Frontiers in Psychiatry. 2013 Jun; 4: 60. doi: 10.3389/fpsyt.2013.00060.

Grayson DR, Kundakovic M, Sharma RP. Is There A Future for Histone Deacetylase Inhibitors in the Pharmacotherapy of Psychiatric Disorders? Molecular Pharmacology. 2010 Feb; 77(2): 126-35. doi: 10.1124/mol.109.061333.

Holliday R. Epigenetics: A Historical Overview. Epigenetics. 2006 Apr; 1(2): 76-80. doi: 10.4161/epi.1.2.2762.

Haroutunian V, Katsel P, Dracheva S, Stewart DG, Davis KL. Variations in Oligodendrocyte-Related Gene Expression Across Multiple Cortical Regions: Implications for the Pathophysiology of Schizophrenia. International Journal of Neuro-psychopharmacology. 2007 Aug; 10(4): 565-73. doi: 10.1017/S1461145706007310.

Takahashi T and Suzuki M. Brain morphologic Changes in Early Stages of Psychosis: Implications for Clinical Application and Early Intervention. Psychiatry and Clinical Neurosciences. 2018 Aug; 72(8): 556-71. doi: 10.1111/pcn.12670.

Lutz PE and Turecki GD. DNA Methylation and Childhood Maltreatment: From Animal Models to Human Studies. Neuroscience. 2014 Apr; 264: 142-56. doi: 10.1016/j.neuroscience.2013.07.069.