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Neuroimmune transcriptome changes in patient brains of psychiatric and neurological disorders

Molecular Psychiatry volume 28, pages 710–721 (2023)Cite this article

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Abstract

Neuroinflammation has been implicated in multiple brain disorders but the extent and the magnitude of change in immune-related genes (IRGs) across distinct brain disorders has not been directly compared. In this study, 1275 IRGs were curated and their expression changes investigated in 2467 postmortem brains of controls and patients with six major brain disorders, including schizophrenia (SCZ), bipolar disorder (BD), autism spectrum disorder (ASD), major depressive disorder (MDD), Alzheimer’s disease (AD), and Parkinson’s disease (PD). There were 865 IRGs present across all microarray and RNA-seq datasets. More than 60% of the IRGs had significantly altered expression in at least one of the six disorders. The differentially expressed immune-related genes (dIRGs) shared across disorders were mainly related to innate immunity. Moreover, sex, tissue, and putative cell type were systematically evaluated for immune alterations in different neuropsychiatric disorders. Co-expression networks revealed that transcripts of the neuroimmune systems interacted with neuronal-systems, both of which contribute to the pathology of brain disorders. However, only a few genes with expression changes were also identified as containing risk variants in genome-wide association studies. The transcriptome alterations at gene and network levels may clarify the immune-related pathophysiology and help to better define neuropsychiatric and neurological disorders.

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Fig. 1: Differential expression of immune genes in six disorders.
Fig. 2: Comparison of the effect size of differentially expressed IRGs among neuropsychiatric disease pairs.
Fig. 3: Comparing dIRG-associated function across disorders.
Fig. 4: Shared immune-related co-expression modules.
Fig. 5: Disease-specific co-expression modules.

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Data availability

All data are available in the main text or the Supplementary Materials.

Code availability

The code of this work can be found at https://github.com/normacyyyyy/IRG-cross-disorder.

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Acknowledgements

Published microarray datasets analyzed in this study are available on Gene Expression Omnibus (accession No. GSE28521, GSE28475, GSE35978, GSE53987, GSE17612, GSE12649, GSE21138, GSE54567, GSE54568, GSE54571, GSE54572, GSE29555, GSE5281, GSE28146, GSE20168, GSE20295, GSE54282, GSE68719 and GSE11223), ArrayExpress (accession no. E-MTAB-184), or directly from the study authors. RNA-seq data (available on Synapse with accession numbers syn4590909 and syn4587609, with access governed by NIMH Repository and Genomics Resource) were generated as part of the PsychENCODE Consortium, supported by grants U01MH103339, U01MH103365, U01MH103392, U01MH103340, U01MH103346, R01MH105472, R01MH094714, R01MH105898, R21MH102791, R21MH105881, R21MH103877, and P50MH106934 awarded to Schahram Akbarian (Icahn School of Medicine at Mount Sinai), Gregory Crawford (Duke), Stella Dracheva (Icahn School of Medicine at Mount Sinai), Peggy Farnham (USC), Mark Gerstein (Yale), Daniel Geschwind (UCLA), Thomas M. Hyde (LIBD), Andrew Jaffe (LIBD), James A. Knowles (USC), Chunyu Liu (SUNY), Dalila Pinto (Icahn School of Medicine at Mount Sinai), Nenad Sestan (Yale), Pamela Sklar (Icahn School of Medicine at Mount Sinai), Matthew State (UCSF), Patrick Sullivan (UNC), Flora Vaccarino (Yale), Sherman Weissman (Yale), Kevin White (UChicago), and Peter Zandi (JHU). RNA-seq data from the CommonMind Consortium used in this study (Synapse accession no. syn2759792) was supported by funding from Takeda Pharmaceuticals Company, F. Hoffman-La Roche and NIH grants R01MH085542, R01MH093725, P50MH066392, P50MH080405, R01MH097276, RO1-MH-075916, P50M096891, P50MH084053S1, R37MH057881, R37MH057881S1, HHSN271201300031C, AG02219, AG05138, and MH06692. RNA-seq data from the ROSMAP were provided by the Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago. Data collection was supported through funding by NIA grants P30AG10161 (ROS), R01AG15819 (ROSMAP; genomics and RNA-seq), R01AG17917 (MAP), R01AG30146, R01AG36042 (5hC methylation, ATACseq), RC2AG036547 (H3K9Ac), R01AG36836 (RNA-seq), R01AG48015 (monocyte RNA-seq) RF1AG57473 (single nucleus RNA-seq), U01AG32984 (genomic and whole exome sequencing), U01AG46152 (ROSMAP AMP-AD, targeted proteomics), U01AG46161(TMT proteomics), U01AG61356 (whole genome sequencing, targeted proteomics, ROSMAP AMP-AD), the Illinois Department of Public Health (ROSMAP), and the Translational Genomics Research Institute (genomic). Brain tissue for the study was obtained from the following brain bank collections: the Mount Sinai NIH Brain and Tissue Repository, the University of Pennsylvania Alzheimer’s Disease Core Center, the University of Pittsburgh NeuroBioBank and Brain and Tissue Repositories, the Harvard Brain Bank as part of the Autism Tissue Project (ATP), the Stanley Medical Research Institute, and the NIMH Human Brain Collection Core. We thank Mingrui Yu, and Yan Xia for reviewing the paper.

Funding

National Natural Science Foundation of China Nos. 82022024. National Natural Science Foundation of China Nos. 31970572. National Natural Science Foundation of China Nos. 31871276. the National Key R&D Project of China Grants No. 2016YFC1306000. the National Key R&D Project of China Grants No. 2017YFC0908701. Innovation-driven Project of Central South University Grant Nos. 2020CX003. NIH grants U01MH122591. NIH grants U01MH116489. NIH grants R01MH110920.

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Authors and Affiliations

  1. Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, and Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, China

    Yu Chen, Jiacheng Dai, Longfei Tang, Qiuman Liang, Miao Li, Jiaqi Zhou, Chao Chen & Chunyu Liu

  2. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Yu Chen

  3. State Key Laboratory of Genetic Engineering, Human Phenome Institute, and School of Life Sciences, Fudan University, Shanghai, China

    Jiacheng Dai

  4. Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, USA

    Tatiana Mikhailova, Richard F. Kopp & Chunyu Liu

  5. Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA

    Cynthia Weickert

  6. School of Psychiatry, UNSW, Sydney, NSW, Australia

    Cynthia Weickert

  7. Hunan Key Laboratory of Animal Models for Human Diseases, Central South University, Changsha, China

    Chao Chen

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  1. Yu Chen
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  10. Chao Chen
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Contributions

Conceptualization: YC, CL. Methodology: YC, JD, LT. Investigation: YC, JD, QL, QH, ML, JZ. Visualization: YC. Funding acquisition: CL, CC. Project administration: CL. Supervision: CL, CC. Writing—original draft: YC, JD, CL, Writing—review ānd editing: YC, CL, JD, T.M., RK, CC,CW.

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Correspondence to Chao Chen or Chunyu Liu.

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Chen, Y., Dai, J., Tang, L. et al. Neuroimmune transcriptome changes in patient brains of psychiatric and neurological disorders. Mol Psychiatry 28, 710–721 (2023). https://doi.org/10.1038/s41380-022-01854-7

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