Whole-genome sequencing reveals that variants in the Interleukin 18 Receptor Accessory Protein 3'UTR protect against ALS.
Whole-genome sequencing reveals that variants in the Interleukin 18 Receptor Accessory Protein 3'UTR protect against ALS.
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DOI：
10.1038/s41593-022-01040-6
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发表时间：
2022-04
影响因子：
25
通讯作者：
Hornstein E
中科院分区：
文献类型：
--
作者：
Eitan C;Siany A;Barkan E;Olender T;van Eijk KR;Moisse M;Farhan SMK;Danino YM;Yanowski E;Marmor-Kollet H;Rivkin N;Yacovzada NS;Hung ST;Cooper-Knock J;Yu CH;Louis C;Masters SL;Kenna KP;van der Spek RAA;Sproviero W;Al Khleifat A;Iacoangeli A;Shatunov A;Jones AR;Elbaz-Alon Y;Cohen Y;Chapnik E;Rothschild D;Weissbrod O;Beck G;Ainbinder E;Ben-Dor S;Werneburg S;Schafer DP;Brown RH Jr;Shaw PJ;Van Damme P;van den Berg LH;Phatnani H;Segal E;Ichida JK;Al-Chalabi A;Veldink JH;Project MinE ALS Sequencing Consortium;NYGC ALS Consortium;Hornstein E
非编码基因组比编码蛋白质的基因组大得多，但在很大程度上还没有被遗传关联研究所探索。在这里，我们对6,139例肌萎缩侧索硬化症(ALS)全基因组和70,403例非肌萎缩侧索硬化症对照全基因组中的25,000个变异进行了基于区域的罕见变异关联分析。我们发现白介素18受体辅助蛋白(IL18RAP)3‘非翻译区(3’UTR)变异在非ALS基因组中显著丰富，与发生ALS的风险降低5倍相关，并在一个独立的队列中复制。IL18RAP 3‘UTR中的这些变异降低了mRNA的稳定性和双链RNA(DsRNA)结合蛋白的结合。最后，IL18RAP 3‘非编码区的变体为运动神经元提供了生存优势，因为它们抑制了人类诱导的多能干细胞来源的小胶质细胞在C9orf72中的神经毒性，该小胶质细胞具有肌萎缩侧索硬化症相关的扩张，这依赖于NF-κB信号。这项研究揭示了通过减少神经炎症来预防ALS的遗传变异，并强调了非编码遗传关联研究的重要性。
The noncoding genome is substantially larger than the protein-coding genome but has been largely unexplored by genetic association studies. Here, we performed region-based rare variant association analysis of >25,000 variants in untranslated regions of 6,139 amyotrophic lateral sclerosis (ALS) whole genomes and the whole genomes of 70,403 non-ALS controls. We identified interleukin-18 receptor accessory protein (IL18RAP) 3′ untranslated region (3′UTR) variants as significantly enriched in non-ALS genomes and associated with a fivefold reduced risk of developing ALS, and this was replicated in an independent cohort. These variants in the IL18RAP 3′UTR reduce mRNA stability and the binding of double-stranded RNA (dsRNA)-binding proteins. Finally, the variants of the IL18RAP 3′UTR confer a survival advantage for motor neurons because they dampen neurotoxicity of human induced pluripotent stem cell (iPSC)-derived microglia bearing an ALS-associated expansion in C9orf72, and this depends on NF-κB signaling. This study reveals genetic variants that protect against ALS by reducing neuroinflammation and emphasizes the importance of noncoding genetic association studies.
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影响因子：
6
作者：
Christian F;Smith EL;Carmody RJ
通讯作者：
Carmody RJ
影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
影响因子：
56.9
作者：
An, Joon-Yong;Lin, Kevin;Sanders, Stephan J.
通讯作者：
Sanders, Stephan J.
影响因子：
5.4
作者：
Buratti, Emanuele;De Conti, Laura;Baralle, Francisco
通讯作者：
Baralle, Francisco
影响因子：
9.3
作者：
Alboni S;Cervia D;Sugama S;Conti B
通讯作者：
Conti B