RNA editing underlies genetic risk of common inflammatory diseases.
RNA editing underlies genetic risk of common inflammatory diseases.
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RNA编辑是常见炎症性疾病的遗传风险。
DOI：
10.1038/s41586-022-05052-x
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发表时间：
2022-08
期刊：
影响因子：
64.8
通讯作者：
Li, Jin Billy
中科院分区：
文献类型：
--
作者：
Li, Qin;Gloudemans, Michael J.;Geisinger, Jonathan M.;Fan, Boming;Aguet, Francois;Sun, Tao;Ramaswami, Gokul;Li, Yang, I;Ma, Jin-Biao;Pritchard, Jonathan K.;Montgomery, Stephen B.;Li, Jin Billy
人类遗传学的一个主要挑战是确定性状相关和疾病相关变异的分子机制。为了实现这一点，具有中间分子表型（例如基因表达和剪接）的遗传变体的数量性状基因座（QTL）作图已被广泛采用。然而，尽管取得了成功，相当一部分性状相关和疾病相关变异的分子基础仍然不清楚。在这里，我们表明，ADAR介导的腺苷到肌苷RNA编辑，一个转录后事件至关重要的抑制细胞双链RNA（dsRNA）介导的先天免疫干扰素反应，是一个重要的潜在机制与常见的炎症性疾病相关的遗传变异。我们在49个人体组织中鉴定并表征了30，319个顺式RNA编辑QTL（edQTL）。这些edQTL在自身免疫和免疫介导的疾病的全基因组关联研究信号中显著富集。edQTL与疾病风险基因座的共定位分析进一步确定了由预期的反向重复Alu元件以及意外的、高度过度表达的顺式天然反义转录物形成的关键的、puploid免疫原性dsRNA。此外，炎性疾病风险变体总体上与附近dsRNA的编辑减少和炎性疾病中诱导的干扰素应答相关。这种独特的定向效应与已建立的机制一致，即缺乏ADAR 1的RNA编辑导致dsRNA传感器MDA 5的特异性激活以及随后的干扰素反应和炎症。我们的研究结果表明，细胞dsRNA编辑和传感是常见炎症性疾病的一种以前未被充分认识的机制。
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. However, despite successes, the molecular basis for a considerable fraction of trait-associated and disease-associated variants remains unclear. 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, 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. Our findings implicate cellular dsRNA editing and sensing as a previously underappreciated mechanism of common inflammatory diseases.
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影响因子：
2.7
作者：
Franzén O;Ermel R;Sukhavasi K;Jain R;Jain A;Betsholtz C;Giannarelli C;Kovacic JC;Ruusalepp A;Skogsberg J;Hao K;Schadt EE;Björkegren JLM
通讯作者：
Björkegren JLM
ADAR1结合的基因组分析及其参与多个RNA处理途径。
影响因子：
16.6
作者：
Bahn, Jae Hoon;Ahn, Jaegyoon;Lin, Xianzhi;Zhang, Qing;Lee, Jae-Hyung;Civelek, Mete;Xiao, Xinshu
通讯作者：
Xiao, Xinshu
影响因子：
30.8
作者：
Finucane HK;Bulik-Sullivan B;Gusev A;Trynka G;Reshef Y;Loh PR;Anttila V;Xu H;Zang C;Farh K;Ripke S;Day FR;ReproGen Consortium;Schizophrenia Working Group of the Psychiatric Genomics Consortium;RACI Consortium;Purcell S;Stahl E;Lindstrom S;Perry JR;Okada Y;Raychaudhuri S;Daly MJ;Patterson N;Neale BM;Price AL
通讯作者：
Price AL
影响因子：
14.9
作者：
Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
通讯作者：
Flicek P
影响因子：
64.5
作者：
Baeza-Centurion, Pablo;Minana, Belen;Lehner, Ben
通讯作者：
Lehner, Ben