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全基因组测序揭示白细胞介素 18 受体辅助蛋白 3'UTR 中的变异可预防 ALS。

Whole-genome sequencing reveals that variants in the Interleukin 18 Receptor Accessory Protein 3'UTR protect against ALS.

机构信息

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.

Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel.

出版信息

Nat Neurosci. 2022 Apr;25(4):433-445. doi: 10.1038/s41593-022-01040-6. Epub 2022 Mar 31.

DOI:10.1038/s41593-022-01040-6
PMID:35361972
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7614916/
Abstract

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.

摘要

非编码基因组的大小远远超过编码蛋白质的基因组，但在遗传关联研究中基本上没有得到探索。在这里，我们对 6139 个肌萎缩侧索硬化症（ALS）全基因组和 70403 个非 ALS 对照者的全基因组中未翻译区域的>25000 个变体进行了基于区域的罕见变异关联分析。我们确定白细胞介素 18 受体辅助蛋白 (IL18RAP) 3'非翻译区 (3'UTR) 变体在非 ALS 基因组中显著富集，并与 ALS 发病风险降低五倍相关，这在一个独立的队列中得到了复制。IL18RAP 3'UTR 中的这些变体降低了 mRNA 的稳定性和双链 RNA (dsRNA)结合蛋白的结合能力。最后，IL18RAP 3'UTR 的变体赋予运动神经元生存优势，因为它们可以减轻携带 C9orf72 中 ALS 相关扩展的人诱导多能干细胞 (iPSC)衍生的小胶质细胞的神经毒性，这取决于 NF-κB 信号。这项研究揭示了通过减少神经炎症来保护 ALS 的遗传变异，并强调了非编码遗传关联研究的重要性。

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