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

Dylan J Kiltschewskij; William R Reay; Michael P Geaghan; Joshua R Atkins; Alexandre Xavier; Xiajie Zhang; Oliver J Watkeys; Vaughan J Carr; Rodney J Scott; Melissa J Green; Murray J Cairns

doi:10.1016/j.biopsych.2023.07.010

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

Biol Psychiatry. 2024 Apr 1;95(7):647-661. doi: 10.1016/j.biopsych.2023.07.010. Epub 2023 Jul 20.

Authors

Affiliations

¹ School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia; Precision Medicine Program, Hunter Medical Research Institute, New Lambton, New South Wales, Australia.
² Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
³ School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia.
⁴ School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia; Centre for Information Based Medicine, Hunter Medical Research Institute, New Lambton, New South Wales, Australia.
⁵ School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia.
⁶ School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia; Department of Psychiatry, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia.
⁷ School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia; School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia.
⁸ School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia; Precision Medicine Program, Hunter Medical Research Institute, New Lambton, New South Wales, Australia. Electronic address: murray.cairns@newcastle.edu.au.

PMID: 37480976
DOI: 10.1016/j.biopsych.2023.07.010

Abstract

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.

Keywords: DNA methylation; ES; EWAS; Epigenetic covariance; Epigenetic score; Epigenome-wide association study; Schizophrenia.

MeSH terms

Australia
DNA Methylation*
Epigenesis, Genetic
Epigenome
Genome-Wide Association Study
Humans
Schizophrenia* / genetics