Subtypes of schizophrenia identified by multi-omic measures associated with dysregulated immune function

Chunyan Luo, Xue Nan Pi, Na Hu, Xiao Wang, Yuan Xiao, Siyi Li, John A. Sweeney, Jeffrey R. Bishop, Qiyong Gong, Dan Xie, Su Lui

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Epigenetic modifications are plausible molecular sources of phenotypic heterogeneity across schizophrenia patients. The current study investigated biological heterogeneity in schizophrenia using peripheral epigenetic profiles to delineate illness subtypes independent of their phenomenological manifestations. We applied epigenome-wide profiling with a DNA methylation array from blood samples of 63 schizophrenia patients and 59 healthy controls. Non-negative matrix factorization (NMF) and k-means clustering were performed to identify DNA methylation-related patient subtypes. The validity of the partition was tested by assessing the profile of the T cell receptor (TCR) repertoires. The uniqueness of the identified subtypes in relation to brain structural and clinical measures were evaluated. Two distinct patterns of DNA methylation profiles were identified in patients. One subtype (60.3% of patients) showed relatively limited changes in methylation levels and cell composition compared to controls, while a second subtype (39.7% of patients) exhibited widespread methylation level alterations among genes enriched in immune cell activity, as well as a higher proportion of neutrophils and lower proportion of lymphocytes. Differentiation of the two patient subtypes was validated by TCR repertoires, which paralleled the partition based on DNA methylation profiles. The subtype with widespread methylation modifications had higher symptom severity, performed worse on cognitive measures, and displayed greater reductions in fractional anisotropy of white matter tracts and evidence of gray matter thickening compared to the other subtype. Identification of a distinct subtype of schizophrenia with unique molecular, cerebral, and clinical features provide a novel parcellation of the schizophrenia syndrome with potential to guide development of individualized therapeutics.

Original languageEnglish (US)
Pages (from-to)6926-6936
Number of pages11
JournalMolecular psychiatry
Issue number11
StatePublished - Nov 2021

Bibliographical note

Funding Information:
This study was supported by National Natural Science Foundation of China (grants 82120108014, 82071908, 81761128023, 81901702 and 81901705); China Postdoctoral Science Foundation (No.2020M673243); Sichuan Science and Technology Program (No. 2021JDTD0002 and 2020YFS0117); 1.3.5 project for disciplines of excellence, Post-Doctoral Research Project, West China Hospital, Sichuan University (Grant: 2ZYJC18020, ZYYC08001, and 018HXBH058) and the University of Cincinnati Schizophrenia Research Fund. LS also acknowledges the support from Humboldt Foundation Friedrich Wihelm Bessel Research Award and Chang Jiang Scholars.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't


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