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Alteration of DNA Methylation and Epigenetic Scores Associated with Features of Schizophrenia and Common Variant Genetic Risk

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posted on 2025-05-10, 20:48 authored by Dylan KiltschewskijDylan Kiltschewskij, William R. Reay, Murray CairnsMurray Cairns, Michael P. Geaghan, Joshua R. Atkins, Alexandre XavierAlexandre Xavier, Xiajie ZhangXiajie Zhang, Oliver J. Watkeys, Vaughan J. Carr, Rodney ScottRodney Scott, Melissa J. Green
Background: Unpacking molecular perturbations associated with features of schizophrenia is a critical step toward understanding phenotypic heterogeneity in this disorder. Recent epigenome-wide association studies have uncovered pervasive dysregulation of DNA methylation in schizophrenia; however, clinical features of the disorder that account for a large proportion of phenotypic variability are relatively underexplored. Methods: We comprehensively analyzed patterns of DNA methylation in a cohort of 381 individuals with schizophrenia from the deeply phenotyped Australian Schizophrenia Research Bank. Epigenetic changes were investigated in association with cognitive status, age of onset, treatment resistance, Global Assessment of Functioning scores, and common variant polygenic risk scores for schizophrenia. We subsequently explored alterations within genes previously associated with psychiatric illness, phenome-wide epigenetic covariance, and epigenetic scores. Results: Epigenome-wide association studies of the 5 primary traits identified 662 suggestively significant (p < 6.72 × 10−5) differentially methylated probes, with a further 432 revealed after controlling for schizophrenia polygenic risk on the remaining 4 traits. Interestingly, we uncovered many probes within genes associated with a variety of psychiatric conditions as well as significant epigenetic covariance with phenotypes and exposures including acute myocardial infarction, C-reactive protein, and lung cancer. Epigenetic scores for treatment-resistant schizophrenia strikingly exhibited association with clozapine administration, while epigenetic proxies of plasma protein expression, such as CCL17, MMP10, and PRG2, were associated with several features of schizophrenia. Conclusions: Our findings collectively provide novel evidence suggesting that several features of schizophrenia are associated with alteration of DNA methylation, which may contribute to interindividual phenotypic variation in affected individuals.

Funding

NHMRC

1147644

1121474

History

Journal title

Biological Psychiatry

Volume

95

Issue

7

Pagination

647-661

Publisher

Elsevier

Language

  • en, English

College/Research Centre

College of Health, Medicine and Wellbeing

School

School of Biomedical Sciences and Pharmacy

Rights statement

© 2023 Society of Biological Psychiatry. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).