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

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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.

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

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.

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

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The authors declare no competing interests.

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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.

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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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