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

Molecular Psychiatry volume 26, pages 6926–6936 (2021)Cite this article

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Abstract

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.

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Fig. 1: Optimal rank determination by NMF.
Fig. 2: Over-representation analysis and cell decomposition.
Fig. 3: TCR repertoires analysis.
Fig. 4: Overlap between DNA methylation subtypes and TCR subtypes.

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Code availability

Analysis code are available upon request to the corresponding authors.

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Funding

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.

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Authors and Affiliations

  1. Huaxi MR Research Center, Department of Radiology and National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, China

    Chunyan Luo, Na Hu, Yuan Xiao, Siyi Li, John A. Sweeney, Qiyong Gong & Su Lui

  2. Psychoradiology Research Unit of the Chinese Academy of Medical Sciences (2018RU011), West China Hospital of Sichuan University, Chengdu, China

    Chunyan Luo, Na Hu, Yuan Xiao, Siyi Li, Qiyong Gong & Su Lui

  3. National Frontier Center of Disease Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China

    XueNan Pi & Dan Xie

  4. The Clinical Hospital of Chengdu Brain Science Institute, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China

    Xiao Wang

  5. Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, OH, 45219, USA

    John A. Sweeney

  6. Department of Experimental and Clinical Pharmacology and Department of Psychiatry and Behavioral Sciences, University of Minnesota, Minneapolis, MN, USA

    Jeffrey R. Bishop

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  1. Chunyan Luo
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Contributions

LS, GQ, XD and LC contributed to study design. LC, XY, HN, LS and WX contributed to acquisition of data. LC, PX and WX contributed to analysis and interpretation of the data. LC and PX contributed to the drafting of the paper. SJ, BJ, LS and XD made critical revision of the paper for important intellectual content. LS, GQ, XD and LC had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

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Correspondence to Qiyong Gong, Dan Xie or Su Lui.

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Luo, C., Pi, X., Hu, N. et al. Subtypes of schizophrenia identified by multi-omic measures associated with dysregulated immune function. Mol Psychiatry 26, 6926–6936 (2021). https://doi.org/10.1038/s41380-021-01308-6

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