RNA editing underlies genetic risk of common inflammatory diseases

Article

关键词: INNATE IMMUNE-RESPONSES;    RHEUMATOID-ARTHRITIS;    COMPLEX TRAITS;    HUMAN ALU;    LANDSCAPE;    ADAR1;    VARIANTS;    IFIH1;    IDENTIFICATION;    DSRNA;   

DOI  :  10.1038/s41586-022-05052-x

来源: SCIE

【 摘 要 】

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 adopted(1,2). However, despite successes, the molecular basis for a considerable fraction of trait-associated and disease-associated variants remains unclear(3,4). 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 responses(5-11), 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 inflammation(7-9). Our findings implicate cellular dsRNA editing and sensing as a previously underappreciated mechanism of common inflammatory diseases. cis-RNA editing quantitative trait loci, which are associated with immunogenic double-stranded RNAs, underlie genome-wide association study variants in common autoimmune and inflammatory diseases.

【 授权许可】

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