Elevated brain-derived cell-free DNA among patients with first psychotic episode - a proof-of-concept study
- The Hebrew University-Hadassah Medical School, Israel
- Jerusalem Mental Health Center, Israel
- Karolinska Institutet Innovations, Sweden
- Hebrew University of Jerusalem, Israel
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 fragments (cfDNA) 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.
Data availability
All relevant data including information on the markers used (coordinates and primer sequences), detailed information on patients and donors and the raw data on values of each methylation marker in each sample is provided in Source data 1. This data was used to generate the graphs shown in the paper.Detailed PCR conditions are detailed in the Materials and methods section and were published in a recent paper. Code is uploaded to GitHub as described in the paper (https://github.com/Joshmoss11/btseq).
Article and author information
Author details
Funding
Award of the National Institute of Psychobiology in Israel and the Israeli Society of Biological Psychiatry
- Asael Lubotzky
Israel Science Foundation
- Yuval Dor
Grail
- Yuval Dor
Award of the National Institute of Psychobiology in Israel and the Israeli Society of Biological Psychiatry
- Ilana Pelov
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Jacky Lam, Chinese University of Hong Kong, Hong Kong
Ethics
Human subjects: This study was conducted according to protocols approved by the Jerusalem Mental Health Center Institutional Review Board, in accordance with the Declaration of Helsinki (HMO-14-0198).We recruited men and women over 18 years of age, who have developed psychotic symptoms for the first time in their life within the last year and were admitted to the acute psychiatric units of the Jerusalem Mental Health Center in Israel.Blood samples were obtained after the initial stabilization and partial remission of the psychotic symptoms which enabled the patients to give written informed consent for participation in the study. The time achieving stability was different for each individual patient, but the majority stabilized within 4 weeks (79%). The patients were asked to complete a short questionnaire regarding demographic details, current physical condition, the onset of present symptoms and drug use. The recruitment was done following the approval of the study's protocol by the Jerusalem Mental Health Center Institutional Review Board. Patients with acute medical conditions in the week prior to the blood sampling were excluded from the study.31 adult volunteers participated in the study as unpaid healthy controls.
Version history
- Received: December 15, 2021
- Preprint posted: February 10, 2022 (view preprint)
- Accepted: June 6, 2022
- Accepted Manuscript published: June 14, 2022 (version 1)
- Version of Record published: June 16, 2022 (version 2)
Copyright
© 2022, Lubotzky et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Elevated brain-derived cell-free DNA among patients with first psychotic episode - a proof-of-concept study
eLife 11:e76391.
https://doi.org/10.7554/eLife.76391
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