DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia

We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.

Automated summary

The study identified differentially methylated positions (DMPs) in blood DNA methylation profiles associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Analysis across datasets revealed DMPs with evidence of colocalization to regions nominated by genetic association studies of the diseases. The findings suggest that DNA methylation data can serve as molecular biomarkers for treatment-resistant schizophrenia and reveal environmental factors associated with psychosis.