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Global landscape and genetic regulation of RNA editing in cortical samples from individuals with schizophrenia

Nature Neuroscience volume 22, pages 1402–1412 (2019)Cite this article

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Abstract

RNA editing critically regulates neurodevelopment and normal neuronal function. The global landscape of RNA editing was surveyed across 364 schizophrenia cases and 383 control postmortem brain samples from the CommonMind Consortium, comprising two regions: dorsolateral prefrontal cortex and anterior cingulate cortex. In schizophrenia, RNA editing sites in genes encoding AMPA-type glutamate receptors and postsynaptic density proteins were less edited, whereas those encoding translation initiation machinery were edited more. These sites replicate between brain regions, map to 3′-untranslated regions and intronic regions, share common sequence motifs and overlap with binding sites for RNA-binding proteins crucial for neurodevelopment. These findings cross-validate in hundreds of non-overlapping dorsolateral prefrontal cortex samples. Furthermore, ~30% of RNA editing sites associate with cis-regulatory variants (editing quantitative trait loci or edQTLs). Fine-mapping edQTLs with schizophrenia risk loci revealed co-localization of eleven edQTLs with six loci. The findings demonstrate widespread altered RNA editing in schizophrenia and its genetic regulation, and suggest a causal and mechanistic role of RNA editing in schizophrenia neuropathology.

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Fig. 1: Overview of the study design and analytic pipeline.
Fig. 2: Overall RNA editing profiles.
Fig. 3: Identification of differentially edited sites in SCZ.
Fig. 4: Genes enriched with differential editing sites that replicate across two brain regions or across two cohorts.
Fig. 5: Unsupervised co-editing network analysis.
Fig. 6: Brain cis-edQTL analysis.
Fig. 7: Coloc2 fine-mapping analysis.

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Data availability

The CMC investigators are committed to the release of data and analysis results, with the anticipation that data sharing in a rapid and transparent manner will speed the pace of research to the benefit of the greater research community. Data and analytical results generated through the CMC are available through the CMC Knowledge Portal: https://doi.org/10.7303/syn2759792.

URLs. HBCC: https://www.nimh.nih.gov/research/research-conducted-at-nimh/research-areas/research-support-services/hbcc/index.shtml

CMC: http://www.synapse.org/CMC

Code availability

Code for identifying RNA editing sites and quantifying RNA editing ratios are provided in the public repository: https://github.com/BreenMS/RNAediting

Differential RNA editing, co-editing network analyses and edQTL analysis used standard software packages.

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Acknowledgements

Data were generated as part of the CommonMind Consortium, supported by funding from Takeda Pharmaceuticals Company Ltd, F. Hoffman-La Roche Ltd and NIH grant nos. R01MH085542, R01MH093725, P50MH066392, P50MH080405, R01MH097276, R01-MH-075916, P50M096891, P50MH084053S1, R37MH057881, AG02219, AG05138, MH06692, R01MH110921, R01MH109677, R01MH109897 and U01MH103392, and contract no. HHSN271201300031C through the NIMH’s Intramural Research Program. 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, and the NIMH HBCC. CMC leadership comprises: P. Roussos, J. D. Buxbaum, A. Chess, S. Akbarian, V. Haroutunian (Icahn School of Medicine at Mount Sinai), B. Devlin, D. Lewis (University of Pittsburgh), R. Gur, C.-G. Hahn (University of Pennsylvania), E. Domenici (University of Trento), M. A. Peters, S. Sieberts (Sage Bionetworks), T. Lehner, G. Senthil, S. Marenco and B. K. Lipska (NIMH). DLPFC RNA-seq data, which formed the basis of the validation cohort, were provided by the NIMH HBCC. Rhesus macaque tissue was provided by S. Hemby through the Stanley Medical Research Institute for Funding for Non-Human Primate Research, and funded by NIMH grant no. R01MH074313.

Author information

Author notes

  1. Deceased: Pamela Sklar.

  2. A full list of authors and affiliations appears at the end of the paper.

Authors and Affiliations

  1. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Michael S. Breen, Panos Roussos, Eli Stahl, Joseph D. Buxbaum, Schahram Akbarian, Jaroslav Bendl, Kristen Brennand, Leanne Brown, Alexander Charney, Lizette Couto, Olivia Devillers, Elie Flatow, John F. Fullard, Sergio Espeso Gil, Kiran Girdhar, Vahram Haroutunian, Laura Huckins, Rivky Jacobov, Yan Jiang, Jessica S. Johnson, Bibi Kassim, Yungil Kim, Royce Park, Chaggai Rosenbluh, Laura Sloofman, Jennifer Wiseman, Wen Zhang & Elizabeth Zharovsky

  2. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Michael S. Breen, Amanda Dobbyn, Panos Roussos, Gabriel E. Hoffman, Eli Stahl, Andrew Chess, Joseph D. Buxbaum, John F. Fullard, Hardik R. Shah & Ying-Chih Wang

  3. Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Michael S. Breen, Joseph D. Buxbaum & Andrew Browne

  4. The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Amanda Dobbyn

  5. Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Amanda Dobbyn, Panos Roussos, Gabriel E. Hoffman, Eli Stahl, Jaroslav Bendl, Kristen Brennand, Alexander Charney, Nancy Francoeur, Kiran Girdhar, Vahram Haroutunian, Laura Huckins, Jessica S. Johnson, Yungil Kim, Laura Sloofman & Wen Zhang

  6. Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA

    Qin Li & Jin Billy Li

  7. Mental Illness Research, Education, and Clinical Center (VISN 2 South), James J. Peters VA Medical Center, Bronx, NY, USA

    Panos Roussos & Vahram Haroutunian

  8. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Panos Roussos, Andrew Chess, Pamela Sklar, Joseph D. Buxbaum & Mads Engel Hauberg

  9. Icahn Institute for Data Science and Genomic Technologies, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Gabriel E. Hoffman, Eli Stahl, Andrew Chess, Pamela Sklar, Hardik R. Shah & Ying-Chih Wang

  10. Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Eli Stahl

  11. Department of Cell Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Andrew Chess, Attila Gulyás-Kovács & Eva Xia

  12. Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Bernie Devlin

  13. Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Joseph D. Buxbaum

  14. Division of Psychiatric Epigenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Schahram Akbarian, Leanne Brown, Lizette Couto, Olivia Devillers, Elie Flatow, John F. Fullard, Sergio Espeso Gil, Rivky Jacobov, Yan Jiang, Bibi Kassim, Lambertus Klei, Royce Park, Jennifer Wiseman & Elizabeth Zharovsky

  15. Center for Genomic & Computational Biology, Duke University, Durham, NC, USA

    Greg Crawford

  16. Laboratory of Neurogenomic Biomarkers, Centre for Integrative Biology, University of Trento, Trento, Italy

    Enrico Domenici, Michele Filosi & Roberto Visintainer

  17. Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Raquel Gur

  18. Neuropsychiatry Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Raquel Gur

  19. Neuropsychiatric Signaling Program, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Chang-Gyu Hahn

  20. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Vahram Haroutunian

  21. Department of Biomedicine, Aarhus University, Aarhus, Denmark

    Mads Engel Hauberg

  22. Human Brain Collection Core, National Institutes of Health, National Institute of Mental Health, Bethesda, MD, USA

    Robin Kramer, Barbara K. Lipska & Stefano Marenco

  23. Department of Mathematics, University of Trento, Trento, Italy

    Mario Lauria

  24. National Institute of Mental Health, Bethesda, MD, USA

    Thomas Lehner & Geetha Senthil

  25. Department of Medicine, Psychiatry and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA

    David A. Lewis & Douglas M. Ruderfer

  26. Sage Bionetworks, Seattle, WA, USA

    Lara M. Mangravite, Kelsey Montgomery, Thanneer Malai Perumal, Mette A. Peters & Solveig K. Sieberts

  27. Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA

    Douglas M. Ruderfer

  28. Center for Genomic and Computational Biology, Duke University, Durham, NC, USA

    Lingyun Song

  29. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Patrick Sullivan

  30. Department of Statistics and Data Science, Carnegie Mellon University, Pittsburgh, PA, USA

    Jiebiao Wang

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  1. Michael S. Breen
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  2. Amanda Dobbyn
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  3. Qin Li
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  4. Panos Roussos
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  5. Gabriel E. Hoffman
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  6. Eli Stahl
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  7. Andrew Chess
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  8. Pamela Sklar
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  9. Jin Billy Li
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  11. Joseph D. Buxbaum
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Consortia

CommonMind Consortium

  • Schahram Akbarian
  • , Jaroslav Bendl
  • , Kristen Brennand
  • , Leanne Brown
  • , Andrew Browne
  • , Alexander Charney
  • , Lizette Couto
  • , Greg Crawford
  • , Olivia Devillers
  • , Enrico Domenici
  • , Michele Filosi
  • , Elie Flatow
  • , Nancy Francoeur
  • , John F. Fullard
  • , Sergio Espeso Gil
  • , Kiran Girdhar
  • , Attila Gulyás-Kovács
  • , Raquel Gur
  • , Chang-Gyu Hahn
  • , Vahram Haroutunian
  • , Mads Engel Hauberg
  • , Laura Huckins
  • , Rivky Jacobov
  • , Yan Jiang
  • , Jessica S. Johnson
  • , Bibi Kassim
  • , Yungil Kim
  • , Lambertus Klei
  • , Robin Kramer
  • , Mario Lauria
  • , Thomas Lehner
  • , David A. Lewis
  • , Barbara K. Lipska
  • , Stefano Marenco
  • , Lara M. Mangravite
  • , Kelsey Montgomery
  • , Royce Park
  • , Thanneer Malai Perumal
  • , Mette A. Peters
  • , Chaggai Rosenbluh
  • , Douglas M. Ruderfer
  • , Geetha Senthil
  • , Hardik R. Shah
  • , Solveig K. Sieberts
  • , Laura Sloofman
  • , Lingyun Song
  • , Patrick Sullivan
  • , Roberto Visintainer
  • , Jiebiao Wang
  • , Ying-Chih Wang
  • , Jennifer Wiseman
  • , Eva Xia
  • , Wen Zhang
  •  & Elizabeth Zharovsky

Contributions

J.D.B., P.S., J.B.L. and M.S.B contributed to experimental design, study design and formulating the research question. J.D.B. and P.S. contributed to the funding of this work. M.S.B., A.D. and Q.L. contributed to data analysis. P.R., G.E.H., E.S., A.C, P.S., B.D. and J.D.B. contributed to leadership and supervision of various aspects of this work. M.S.B. and J.D.B. contributed to writing the manuscript, and all authors contributed in completing the final version.

Corresponding authors

Correspondence to Michael S. Breen or Joseph D. Buxbaum.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information: Nature Neuroscience thanks T. Kato, J. Yang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Figs. 1–18.

Reporting Summary

Supplementary Table 1

Description of RNA editing events.

Supplementary Table 2

Overlap of RNA editing events across brain regions and cohorts.

Supplementary Table 3

Motif enrichment analysis.

Supplementary Table 4

RBP enrichment analysis.

Supplementary Table 5

Genes enriched for differential RNA editing sites.

Supplementary Table 6

Overlap of co-editing models across brain regions and cohorts.

Supplementary Table 7

Co-localization analysis (coloc2) using 108 SCZ GWAS loci.

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Breen, M.S., Dobbyn, A., Li, Q. et al. Global landscape and genetic regulation of RNA editing in cortical samples from individuals with schizophrenia. Nat Neurosci 22, 1402–1412 (2019). https://doi.org/10.1038/s41593-019-0463-7

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