Methylomic Alteration in Peripheral Blood Lymphocytes of Prodromal Stage and First-Episode Chinese Han Schizophrenia Patients

Abstract

Background: Although epigenetic dysregulation predisposes the onset of schizophrenia, the methylomic changes across the whole genome in psychosis risk syndrome (PRS) and first-episode schizophrenia (FES) is yet fully established in Chinese Han population. \n \nMethods: Peripheral blood lymphocytes were obtained from 81 PRS individuals, 88 FES patients and 62 healthy controls (HC). The set of cases was further divided into discovery (n=135) and validation (n=96) cohorts, balanced for age and sex of individuals. The DNA methylation status of 850,000 CpG sites were analyzed and the methylation profiles of target genes were validated using Infinium Human Methylation 850 BeadChip Array and MethylTarget sequencing approach respectively. \n \nFindings: We detected 372 differently methylated sites between PRS and HC which increased to 460 sites in FES with 207 sites shared. These shared loci were annotated to 148 genes with the majority (128/148) involved in epigenetic regulation or neurodevelopment. Specifically, we identified and validated a robust hypomethylation of SYNGAP1, one of the mostly studied genes responsible for a spectrum of neurodevelopmental disorders. \n \nInterpretation: Our study described an overall hypomethylated landscape in gene body which correctly differentiates both PRS or FES from HC. The hypomethylated SYNGAP1, combined with other clinical, cellular and genetic factors, could be useful for the early diagnosis and management of risk people. \n \nFunding Information: This research was supported by the grant 2016YFC1306900 from the National Key Research and Development Program to Dr. Jingping Zhao, and grants 81630033 and 81471363 to Dr. Jingping Zhao and grant 81622018 to Dr. Renrong Wu, from the National Natural Science Foundation of China, and NIH grant 1R01MH101043 to Dr. Alessandro Guidotti, and Stanley foundation grant Z01 to Dr. Jingping Zhao and Dr. Hua Jin. \n \nDeclaration of Interests: The authors declare no conflict of interest. \n \nEthics Approval Statement: Written informed consent was obtained from all participants, and the study was approved by the second Xiangya Hospital Ethical Committee and review boards of all other participating institutions.