Whole-genome sequencing reveals that variants in the Interleukin 18 Receptor Accessory Protein 3'UTR protect against ALS.
Journal
Nature neuroscience
ISSN: 1546-1726
Titre abrégé: Nat Neurosci
Pays: United States
ID NLM: 9809671
Informations de publication
Date de publication:
04 2022
04 2022
Historique:
received:
22
04
2020
accepted:
16
02
2022
pubmed:
2
4
2022
medline:
9
4
2022
entrez:
1
4
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35361972
doi: 10.1038/s41593-022-01040-6
pii: 10.1038/s41593-022-01040-6
pmc: PMC7614916
mid: EMS184427
doi:
Substances chimiques
3' Untranslated Regions
0
IL18RAP protein, human
0
Interleukin-18 Receptor beta Subunit
0
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
433-445Subventions
Organisme : Medical Research Council
ID : MR/R024804/1
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Organisme : NINDS NIH HHS
ID : R01 NS111990
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS097850
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS073873
Pays : United States
Organisme : Medical Research Council
ID : MR/L501529/1
Pays : United Kingdom
Organisme : Motor Neurone Disease Association
ID : ALCHALABI-DOBSON/APR14/829-791
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NINDS NIH HHS
ID : R01 NS104022
Pays : United States
Investigateurs
Johnathan Cooper-Knock
(J)
Kevin P Kenna
(KP)
Philip Van Damme
(P)
Leonard H van den Berg
(LH)
Eran Hornstein
(E)
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
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