Chen J, Zang Z, Braun U, et al. - This study was conducted to distinguish an epigenetic signature (quantified as polymethylation score [PMS]) of schizophrenia using machine learning applied to genome-wide blood DNA-methylation data; assess whether differences in blood-derived PMS are mirrored in data from postmortem brain samples; test whether the PMS is associated with alterations of dorsolateral prefrontal cortex hippocampal (DLPFC-HC) connectivity during working memory in healthy controls (HC); examine the correlation between interactions between polygenic and epigenetic risk with DLPFC-HC connectivity, and inquire the specificity of the signature compared with other serious psychiatric disorders. Researchers performed a case-control study between 2008 and 2018 in sites in Germany, the United Kingdom, the United States, and Australia including a total of 7,488 individuals (4,395 men [58.7%]), of whom 3158 (2,230 men [70.6%]) received a diagnosis of schizophrenia. They distinguished a reproducible blood DNA-methylation signature specific for schizophrenia that was associated with changed functional DLPFC-HC coupling during working memory and mapped to methylation differences found in DLPFC postmortem samples. The results of this study demonstrate a possible epigenetic contribution to a schizophrenia intermediate phenotype and recommend that PMS could be of interest to be studied in the context of multimodal biomarkers for disease stratification and treatment personalization.