Elevated brain-derived cell-free DNA among patients with first psychotic episode – a proof-of-concept study
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Curated by eLife
Evaluation Summary:
This study explores the utility of cell free DNA analysis in non-malignant disease using epigenomic methods. By using brain specific methylation loci the authors identify higher levels of brain-related DNA in the plasma of patients with acute psychotic illness compared with non-disease controls. This paper will be of interest to readers in the field of liquid biopsy.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Abstract
Schizophrenia is a common, severe, and debilitating psychiatric disorder. Despite extensive research there is as yet no biological marker that can aid in its diagnosis and course prediction. This precludes early detection and intervention. Imaging studies suggest brain volume loss around the onset and over the first few years of schizophrenia, and apoptosis has been proposed as the underlying mechanism. Cell-free DNA (cfDNA) fragments are released into the bloodstream following cell death. Tissue-specific methylation patterns allow the identification of the tissue origins of cfDNA. We developed a cocktail of brain-specific DNA methylation markers, and used it to assess the presence of brain-derived cfDNA in the plasma of patients with a first psychotic episode. We detected significantly elevated neuron- (p=0.0013), astrocyte- (p=0.0016), oligodendrocyte- (p=0.0129), and whole brain-derived (p=0.0012) cfDNA in the plasma of patients during their first psychotic episode (n=29), compared with healthy controls (n=31). Increased cfDNA levels were not correlated with psychotropic medications use. Area under the curve (AUC) was 0.77, with 65% sensitivity at 90% specificity in patients with a psychotic episode. Potential interpretations of these findings include increased brain cell death, disruption of the blood-brain barrier, or a defect in clearance of material from dying brain cells. Brain-specific cfDNA methylation markers can potentially assist early detection and monitoring of schizophrenia and thus allow early intervention and adequate therapy.
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Evaluation Summary:
This study explores the utility of cell free DNA analysis in non-malignant disease using epigenomic methods. By using brain specific methylation loci the authors identify higher levels of brain-related DNA in the plasma of patients with acute psychotic illness compared with non-disease controls. This paper will be of interest to readers in the field of liquid biopsy.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
In this study, the authors have analysed the contribution of brain-derived cell-free DNA in the blood of patients with psychosis based on the established methylation-based tissue deconvolution methodology. Using tissue- or cell-type methylation marker, they have demonstrated a higher level of brain-derived cell-free DNA in patients who experienced psychotic symptoms compared to healthy controls. The finding would serve as a proof of concept for the methylation analysis of cell-free DNA in psychosis.
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Reviewer #2 (Public Review):
The authors correlate levels of brain cell specific methylation loci in cell free DNA isolated from plasma with the onset of psychotic symptoms in schizophrenia. The outline of the study is clear and concise and the methods build upon established techniques in a novel cohort of patients.
They have identified a collection of genomic loci that can be identified as deriving from the brain when unmethylated. Thus, they provide a method for easy and cheap detection of brain derived DNA in the circulation.
Whilst the cohort size studied is small it is in keeping with those previously published in similar studies. They have set out to provide 'proof of concept' regarding the use of biomarkers for diagnosis and prognostication in schizophrenia. Whilst they provide interesting data on the presence of brain derived …
Reviewer #2 (Public Review):
The authors correlate levels of brain cell specific methylation loci in cell free DNA isolated from plasma with the onset of psychotic symptoms in schizophrenia. The outline of the study is clear and concise and the methods build upon established techniques in a novel cohort of patients.
They have identified a collection of genomic loci that can be identified as deriving from the brain when unmethylated. Thus, they provide a method for easy and cheap detection of brain derived DNA in the circulation.
Whilst the cohort size studied is small it is in keeping with those previously published in similar studies. They have set out to provide 'proof of concept' regarding the use of biomarkers for diagnosis and prognostication in schizophrenia. Whilst they provide interesting data on the presence of brain derived DNA in the plasma of those with acute psychosis, significant further work is required to identify whether this concept is useful and reproducible enough to eventually become a biomarker for this disease.
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