UMass Chan Medical School Faculty Publications

Title

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

UMMS Affiliation

Department of Neurobiology, Brudnick Neuropsychiatric Research Institute; Department of Neurology; Schafer Lab

Publication Date

2022-03-31

Document Type

Article

Disciplines

Computational Biology | Computational Neuroscience | Nervous System Diseases | Nucleic Acids, Nucleotides, and Nucleosides

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-kappaB signaling. This study reveals genetic variants that protect against ALS by reducing neuroinflammation and emphasizes the importance of noncoding genetic association studies.

Keywords

Amyotrophic lateral sclerosis, Genetics of the nervous system, Genome-wide association studies, Neuroimmunology

DOI of Published Version

10.1038/s41593-022-01040-6

Source

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. Whole-genome sequencing reveals that variants in the Interleukin 18 Receptor Accessory Protein 3'UTR protect against ALS. Nat Neurosci. 2022 Apr;25(4):433-445. doi: 10.1038/s41593-022-01040-6. Epub 2022 Mar 31. PMID: 35361972. Link to article on publisher's site

Comments

Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

Nature neuroscience

PubMed ID

35361972

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