RNA editing underlies genetic risk of common inflammatory diseases

Qin Li, Michael J. Gloudemans, Jonathan M. Geisinger, Boming Fan, François Aguet, Tao Sun, Gokul Ramaswami, Yang I. Li, Jin-Biao Ma, Jonathan K. Pritchard, Stephen B. Montgomery and Jin Billy Li ()
Additional contact information
Qin Li: Stanford University
Michael J. Gloudemans: Stanford University
Jonathan M. Geisinger: Stanford University
Boming Fan: Fudan University
François Aguet: Broad Institute of MIT and Harvard
Tao Sun: Stanford University
Gokul Ramaswami: Stanford University
Yang I. Li: Stanford University
Jin-Biao Ma: Fudan University
Jonathan K. Pritchard: Stanford University
Stephen B. Montgomery: Stanford University
Jin Billy Li: Stanford University

Nature, 2022, vol. 608, issue 7923, 569-577

Abstract: Abstract A major challenge in human genetics is to identify the molecular mechanisms of trait-associated and disease-associated variants. To achieve this, quantitative trait locus (QTL) mapping of genetic variants with intermediate molecular phenotypes such as gene expression and splicing have been widely adopted1,2. However, despite successes, the molecular basis for a considerable fraction of trait-associated and disease-associated variants remains unclear3,4. Here we show that ADAR-mediated adenosine-to-inosine RNA editing, a post-transcriptional event vital for suppressing cellular double-stranded RNA (dsRNA)-mediated innate immune interferon responses5–11, is an important potential mechanism underlying genetic variants associated with common inflammatory diseases. We identified and characterized 30,319 cis-RNA editing QTLs (edQTLs) across 49 human tissues. These edQTLs were significantly enriched in genome-wide association study signals for autoimmune and immune-mediated diseases. Colocalization analysis of edQTLs with disease risk loci further pinpointed key, putatively immunogenic dsRNAs formed by expected inverted repeat Alu elements as well as unexpected, highly over-represented cis-natural antisense transcripts. Furthermore, inflammatory disease risk variants, in aggregate, were associated with reduced editing of nearby dsRNAs and induced interferon responses in inflammatory diseases. This unique directional effect agrees with the established mechanism that lack of RNA editing by ADAR1 leads to the specific activation of the dsRNA sensor MDA5 and subsequent interferon responses and inflammation7–9. Our findings implicate cellular dsRNA editing and sensing as a previously underappreciated mechanism of common inflammatory diseases.

Date: 2022
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DOI: 10.1038/s41586-022-05052-x

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