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Large-scale analysis of DNA methylation identifies cellular alterations in blood from psychosis patients and molecular biomarkers of treatment-resistant schizophrenia
- Publication Year :
- 2020
- Publisher :
- Cold Spring Harbor Laboratory, 2020.
-
Abstract
- ObjectivePsychosis - a complex and heterogeneous neuropsychiatric condition characterized by hallucinations and delusions - is a common feature of schizophrenia. There is evidence for altered DNA methylation (DNAm) associated with schizophrenia in both brain and peripheral tissues. We aimed to undertake a systematic analysis of variable DNAm associated with psychosis, schizophrenia, and treatment-resistant schizophrenia, also exploring measures of biological ageing, smoking, and blood cell composition derived from DNAm data to identify molecular biomarkers of disease.MethodsWe quantified DNAm across the genome in blood samples from 4,483 participants from seven case-control cohorts including patients with schizophrenia or first-episode psychosis. Measures of biological age, cellular composition and smoking status were derived from DNAm data using established algorithms. DNAm and derived measures were analyzed within each cohort and the results combined by meta-analysis.ResultsPsychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNAm data, with the largest differences seen in treatment-resistant schizophrenia patients. DNAm at 95 CpG sites was significantly different between psychosis cases and controls, with 1,048 differentially methylated positions (DMPs) identified between schizophrenia cases and controls. Schizophrenia-associated DMPs colocalize to regions identified in genetic association studies, with genes annotated to these sites enriched for pathways relevant to disease. Finally, a number of the schizophrenia associated differences were only present in the treatment-resistant schizophrenia subgroup.ConclusionsWe show that DNAm data can be leveraged to derive measures of blood cell counts and smoking that are strongly associated with psychosis. Our DNAm meta-analysis identified multiple DMPs associated with both psychosis and a more refined diagnosis of schizophrenia, with evidence for differential methylation associated with treatment-resistant schizophrenia that potentially reflects exposure to clozapine.
- Subjects :
- Oncology
0303 health sciences
medicine.medical_specialty
Psychosis
business.industry
dNaM
Disease
medicine.disease
3. Good health
03 medical and health sciences
0302 clinical medicine
Schizophrenia
Internal medicine
DNA methylation
mental disorders
medicine
business
030217 neurology & neurosurgery
Clozapine
030304 developmental biology
Genetic association
medicine.drug
Diagnosis of schizophrenia
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....cdf75fdff9a1bd08deb383db1f319ba4
- Full Text :
- https://doi.org/10.1101/2020.04.05.026211