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Amygdala and anterior cingulate transcriptomes from individuals with bipolar disorder reveal downregulated neuroimmune and synaptic pathways

Nature Neuroscience volume 25, pages 381–389 (2022)Cite this article

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Abstract

Recent genetic studies have identified variants associated with bipolar disorder (BD), but it remains unclear how brain gene expression is altered in BD and how genetic risk for BD may contribute to these alterations. Here, we obtained transcriptomes from subgenual anterior cingulate cortex and amygdala samples from post-mortem brains of individuals with BD and neurotypical controls, including 511 total samples from 295 unique donors. We examined differential gene expression between cases and controls and the transcriptional effects of BD-associated genetic variants. We found two coexpressed modules that were associated with transcriptional changes in BD: one enriched for immune and inflammatory genes and the other with genes related to the postsynaptic membrane. Over 50% of BD genome-wide significant loci contained significant expression quantitative trait loci (QTL) (eQTL), and these data converged on several individual genes, including SCN2A and GRIN2A. Thus, these data implicate specific genes and pathways that may contribute to the pathology of BD.

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Fig. 1: Summary of significant differentially expressed features (FDR < 5%) overall and by brain region.
Fig. 2: Results of WGCNA analysis.
Fig. 3: Summary of eQTL and sQTL (FDR < 1%) in loci suggested by the PGC GWAS of BP.
Fig. 4: Gene-visualization plots and accompanying SNP–feature scatterplots for the lead SNP with significant eQTL and/or sQTL (FDR < 1%).
Fig. 5: Scatterplot of Z-score test statistics from the TWAS of genes in the sACC versus the amygdala.

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Data availability

All data generated in this study are made available through the PsychENCODE Consortium. Access to the data is managed by the NIMH Repository and Genomics Resource, and the data are distributed via Synapse under the BipSeq study (syn5844980). Instructions for accessing the data through the NIMH Repository and Genomics Resource are provided here: https://www.nimhgenetics.org/resources/psychencode. More information about browsing the available data and instructions for accessing the data are also provided in the PsychENCODE Knowledge Portal at https://psychencode.synapse.org/.

Code availability

Code for all analyses described here is available on GitHub at https://github.com/LieberInstitute/zandiHyde_bipolar_rnaseq. The code has also been submitted to Zenodo at https://doi.org/10.5281/zenodo.4463984.

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Acknowledgements

This work was supported by a grant from the National Institute of Mental Health (R01MH105898). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We gratefully acknowledge the contributions of the Offices of the Chief Medical Examiner of Maryland, Washington, DC and Northern Virginia for collaborating in the accession of post-mortem human brain donations that were used in this study. L.B. Bigelow and members of the Neuropathology Section of the LIBD made important contributions to the clinical characterization and diagnosis of donors. B. Barry also contributed to analyses of the RNA-seq data. Finally, we express our gratitude to families of the brain donors whose generosity made this study possible.

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Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Peter P. Zandi, Andrew E. Jaffe, Fernando S. Goes, Yian Lin, Christopher A. Ross, Joel E. Kleinman, Daniel R. Weinberger & Thomas M. Hyde

  2. Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Peter P. Zandi & Andrew E. Jaffe

  3. The Lieber Institute for Brain Development, Baltimore, MD, USA

    Andrew E. Jaffe, Emily E. Burke, Leonardo Collado-Torres, Louise Huuki-Myers, Arta Seyedian, Joel E. Kleinman, Daniel R. Weinberger & Thomas M. Hyde

  4. Center for Computational Biology, Johns Hopkins University, Baltimore, MD, USA

    Andrew E. Jaffe & Leonardo Collado-Torres

  5. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Andrew E. Jaffe & Daniel R. Weinberger

  6. Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Andrew E. Jaffe

  7. Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Andrew E. Jaffe & Christopher A. Ross

  8. The National Heart, Lung and Blood Institute, the National Institute of Health, Bethesda, MD, USA

    Fayaz Seifuddin & Mehdi Pirooznia

  9. Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Christopher A. Ross, Daniel R. Weinberger & Thomas M. Hyde

  10. Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Christopher A. Ross

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  1. Peter P. Zandi
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Contributions

P.P.Z. contributed to the study design, data analysis and data interpretation, and he led writing the manuscript. A.E.J. contributed to study design, data processing, data analysis and writing the manuscript. L.C.-T. contributed to data processing, data analysis and writing the manuscript. F.S. and M.P. contributed to data analysis and data interpretation. E.E.B., L.H.-M., A.S. and Y.L. contributed to data analysis. C.A.R. contributed to data interpretation and writing the manuscript. T.M.H. and J.E.K. contributed to study design, data collection and generation, data interpretation and writing the manuscript. D.R.W. and F.S.G. contributed to study design, data interpretation and writing the manuscript. All authors have approved the manuscript and agreed to take responsibility for their contribution to the work.

Corresponding authors

Correspondence to Peter P. Zandi or Thomas M. Hyde.

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Competing interests

A.E.J. is now a full-time employee and shareholder of Neumora Therapeutics, a for-profit biotechnology company, which is unrelated to the contents of this manuscript. D.R.W. is on the scientific advisory board of Sage Therapeutics. All other authors report no competing interests.

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Zandi, P.P., Jaffe, A.E., Goes, F.S. et al. Amygdala and anterior cingulate transcriptomes from individuals with bipolar disorder reveal downregulated neuroimmune and synaptic pathways. Nat Neurosci 25, 381–389 (2022). https://doi.org/10.1038/s41593-022-01024-6

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