Whole-genome sequencing reveals that variants in the Interleukin 18 Receptor Accessory Protein 3'UTR protect against ALS
Department of Neurobiology, Brudnick Neuropsychiatric Research Institute; Department of Neurology; Schafer Lab
Computational Biology | Computational Neuroscience | Nervous System Diseases | Nucleic Acids, Nucleotides, and Nucleosides
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.
Amyotrophic lateral sclerosis, Genetics of the nervous system, Genome-wide association studies, Neuroimmunology
DOI of Published Version
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
Eitan C, Werneburg S, Schafer DP, Brown RH, Hornstein E. (2022). Whole-genome sequencing reveals that variants in the Interleukin 18 Receptor Accessory Protein 3'UTR protect against ALS. UMass Chan Medical School Faculty Publications. https://doi.org/10.1038/s41593-022-01040-6. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/2199