Eitan, C. orcid.org/0000-0001-6952-0336, Siany, A., Barkan, E. et al. (46 more authors) (2022) Whole-genome sequencing reveals that variants in the Interleukin 18 receptor accessory protein 3′UTR protect against ALS. Nature Neuroscience, 25 (4). pp. 433-445. ISSN 1097-6256
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.
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Copyright, Publisher and Additional Information: | © 2022 The Author(s), under exclusive licence to Springer Nature America, Inc. This is an author-produced version of a paper subsequently published in Nature neuroscience . Uploaded in accordance with the publisher's self-archiving policy. | ||||
Keywords: | Amyotrophic lateral sclerosis; Genetics of the nervous system; Genome-wide association studies; Neuroimmunology | ||||
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Institution: | The University of Sheffield | ||||
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield) |
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Depositing User: | Symplectic Sheffield | ||||
Date Deposited: | 14 Aug 2023 11:20 | ||||
Last Modified: | 14 Aug 2023 11:20 | ||||
Status: | Published | ||||
Publisher: | Springer Science and Business Media LLC | ||||
Refereed: | Yes | ||||
Identification Number: | https://doi.org/10.1038/s41593-022-01040-6 | ||||
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