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dc.contributor.authorEitan, Chen
dc.contributor.authorWerneburg, Sebastian
dc.contributor.authorSchafer, Dorothy P.
dc.contributor.authorBrown, Robert H. Jr.
dc.contributor.authorHornstein, Eran
dc.date2022-08-11T08:08:34.000
dc.date.accessioned2022-08-23T15:59:41Z
dc.date.available2022-08-23T15:59:41Z
dc.date.issued2022-03-31
dc.date.submitted2022-05-05
dc.identifier.citation<p>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. <a href="https://doi.org/10.1038/s41593-022-01040-6">Link to article on publisher's site</a></p>
dc.identifier.issn1097-6256 (Linking)
dc.identifier.doi10.1038/s41593-022-01040-6
dc.identifier.pmid35361972
dc.identifier.urihttp://hdl.handle.net/20.500.14038/30728
dc.description<p>Full author list omitted for brevity. For the full list of authors, see article.</p>
dc.description.abstractThe 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.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=35361972&dopt=Abstract">Link to Article in PubMed</a></p>
dc.relation.urlhttps://doi.org/10.1038/s41593-022-01040-6
dc.subjectAmyotrophic lateral sclerosis
dc.subjectGenetics of the nervous system
dc.subjectGenome-wide association studies
dc.subjectNeuroimmunology
dc.subjectComputational Biology
dc.subjectComputational Neuroscience
dc.subjectNervous System Diseases
dc.subjectNucleic Acids, Nucleotides, and Nucleosides
dc.titleWhole-genome sequencing reveals that variants in the Interleukin 18 Receptor Accessory Protein 3'UTR protect against ALS
dc.typeArticle
dc.source.journaltitleNature neuroscience
dc.source.volume25
dc.source.issue4
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/faculty_pubs/2199
dc.identifier.contextkey29018206
html.description.abstract<p>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.</p>
dc.identifier.submissionpathfaculty_pubs/2199
dc.contributor.departmentSchafer Lab
dc.contributor.departmentDepartment of Neurology
dc.contributor.departmentDepartment of Neurobiology, Brudnick Neuropsychiatric Research Institute
dc.source.pages433-445


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