ArticleNature neuroscience2022
Whole-genome sequencing reveals that variants in the Interleukin 18 Receptor Accessory Protein 3'UTR protect against ALS.
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Article in Nature neuroscience, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers, 1 of them a synthesis that pooled it.
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28citing papers in PubMed, 1 pooled it
4.7field-weighted citation impact, top 4% of its field
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Who cites it
28 citing papers in PubMed, 1 synthesis or guideline pooled it, 39 citations in OpenAlex.
- A systematic review and functionalFrontiers in neuroscience · 2025Pooled it
- 3'UTR variants of ALS-linked RNAs modify subcellular and cellular phenotypes.The FEBS journal · 2026Article
- IsomiR Utility in Amyotrophic Lateral Sclerosis Prognostication.medRxiv : the preprint server for health sciences · 2025Article
- IL7RBrain and behavior · 2025Article
- The immune receptor SLAMF5 regulates myeloid-cell mediated neuroinflammation in multiple sclerosis.PLoS biology · 2025Article
- Amyotrophic lateral sclerosis represents corticomotoneuronal system failure.Muscle & nerve · 2025Review
- CREB3 gain of function variants protect against ALS.Nature communications · 2025Article
- Review
- Impact of rare non-coding variants on human diseases through alternative polyadenylation outliers.Nature communications · 2025Article
- Machine learning identified novel players in lipid metabolism, endosomal trafficking, and iron metabolism of the ALS spinal cord.Scientific reports · 2025Article
- Investigation of the role of miRNA variants in neurodegenerative brain diseases.Frontiers in genetics · 2025Article
- Systematic assessment of COVID-19 host genetics using whole genome sequencing data.PLoS pathogens · 2024Article
- Massively parallel screen uncovers many rare 3' UTR variants regulating mRNA abundance of cancer driver genes.Nature communications · 2024Article
- Article
- Pathomechanistic Networks of Motor System Injury in Amyotrophic Lateral Sclerosis.Current neuropharmacology · 2024Review
- Unsupervised machine learning identifies distinct ALS molecular subtypes in post-mortem motor cortex and blood expression data.Acta neuropathologica communications · 2023Article
- Distinct neuroinflammatory signatures exist across genetic and sporadic amyotrophic lateral sclerosis cohorts.Brain : a journal of neurology · 2023Article
- Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets.Signal transduction and targeted therapy · 2023Review
- Amyotrophic lateral sclerosis: translating genetic discoveries into therapies.Nature reviews. Genetics · 2023Review
- Loss of function of the ALS-associated NEK1 kinase disrupts microtubule homeostasis and nuclear import.Science advances · 2023Article
Corrections and comments
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Authors and funding
46 authors at 10 institutions in 6 countries.
Chen Eitan *Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.ORCID http://orcid.org/0000-0001-6952-0336
Aviad Siany *Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Elad BarkanDepartment of Computer Science And Applied Math, Weizmann Institute of Science, Rehovot, Israel.
Tsviya OlenderDepartment of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Kristel R van EijkDepartment of Neurology, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.
Matthieu MoisseKU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology, Leuven, Belgium.ORCID http://orcid.org/0000-0001-8880-9311
Sali M K FarhanAnalytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Yehuda M DaninoDepartment of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Eran YanowskiDepartment of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Hagai Marmor-KolletDepartment of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Natalia RivkinDepartment of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Nancy Sarah YacovzadaDepartment of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.ORCID http://orcid.org/0000-0002-5152-8775
Shu-Ting HungDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Johnathan Cooper-KnockSheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.ORCID http://orcid.org/0000-0002-0873-8689
Chien-Hsiung YuInflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
Cynthia LouisInflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.ORCID http://orcid.org/0000-0001-8382-6358
Seth L MastersInflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.ORCID http://orcid.org/0000-0003-4763-576X
Kevin P KennaDepartment of Neurology, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.
Rick A A van der SpekDepartment of Neurology, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.
William SprovieroKing's College London, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology & Neuroscience, De Crespigny Park, London, United Kingdom.
Ahmad Al KhleifatKing's College London, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology & Neuroscience, De Crespigny Park, London, United Kingdom.ORCID http://orcid.org/0000-0002-7406-9831
Alfredo IacoangeliKing's College London, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology & Neuroscience, De Crespigny Park, London, United Kingdom.
Aleksey ShatunovKing's College London, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology & Neuroscience, De Crespigny Park, London, United Kingdom.
Ashley R JonesKing's College London, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology & Neuroscience, De Crespigny Park, London, United Kingdom.ORCID http://orcid.org/0000-0003-0470-0058
Yael Elbaz-AlonDepartment of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.ORCID http://orcid.org/0000-0002-6267-9800
Yahel CohenDepartment of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Elik ChapnikDepartment of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Daphna RothschildDepartment of Computer Science And Applied Math, Weizmann Institute of Science, Rehovot, Israel.ORCID http://orcid.org/0000-0002-0872-8624
Omer WeissbrodDepartment of Computer Science And Applied Math, Weizmann Institute of Science, Rehovot, Israel.
Gilad BeckDepartment of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel.
Elena AinbinderDepartment of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel.
Shifra Ben-DorDepartment of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel.ORCID http://orcid.org/0000-0001-9604-1939
Sebastian WerneburgDepartment of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA.
Dorothy P SchaferDepartment of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA.
Robert H BrownDepartment of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.ORCID http://orcid.org/0000-0001-6062-1528
Pamela J ShawSheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
Philip Van DammeKU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology, Leuven, Belgium.ORCID http://orcid.org/0000-0002-4010-2357
Leonard H van den BergDepartment of Neurology, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.
Hemali PhatnaniCenter for Genomics of Neurodegenerative Disease, New York Genome Center, New York, USA.
Eran SegalDepartment of Computer Science And Applied Math, Weizmann Institute of Science, Rehovot, Israel.ORCID http://orcid.org/0000-0002-6859-1164
Justin K IchidaDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Ammar Al-ChalabiKing's College London, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology & Neuroscience, De Crespigny Park, London, United Kingdom.ORCID http://orcid.org/0000-0002-4924-7712
Jan H VeldinkDepartment of Neurology, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.ORCID http://orcid.org/0000-0001-5572-9657
Project MinE ALS Sequencing Consortium
NYGC ALS Consortium
Eran HornsteinDepartment of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel. Eran.hornstein@weizmann.ac.il.ORCID http://orcid.org/0000-0002-5534-1924
Weizmann Institute of Science · ILUtrecht University · NLKing's College London · GBThe University of Melbourne · AUUniversity of Massachusetts Chan Medical School · USUniversity of Sheffield · GBVIB-KU Leuven Center for Brain & Disease Research · BEUniversity of Southern California · USBroad Institute · USNew York Genome Center · US
Funding
Expanding the chemical diversity of therapeutic oligonucleotides to treat neurodegenerative disordersR01NS104022 · NINDS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI ANASTASIA KHVOROVA · 2017 to 2026
$6.0MValidating Secretory Autophagy as a Therapeutic Strategy for Diverse Forms of ALS and FTDR01NS097850 · NINDS · UNIVERSITY OF SOUTHERN CALIFORNIA · PI ICHIDA, JUSTIN KAWIKA · 2016 to 2024
$5.5MNext-generation antisense therapeutics for ALS and frontotemporal dementiaR01NS111990 · NINDS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI Robert H Brown, Jonathan K Watts · 2019 to 2026
$5.2MIdentification of genes causative for familial ALS gene using exome sequencingR01NS073873 · NINDS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI LANDERS, JOHN E · 2011 to 2019
$4.6MDepartment of HealthMedical Research Council MR/L501529/1Medical Research Council MR/R024804/1Motor Neurone Disease Association ALCHALABI-DOBSON/APR14/829-791NINDS NIH HHS R01 NS073873NINDS NIH HHS R01 NS097850NINDS NIH HHS R01 NS104022NINDS NIH HHS R01 NS111990Wellcome Trust
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.
Indexed as
Amyotrophic Lateral SclerosisInduced Pluripotent Stem Cells3' Untranslated RegionsHumansInterleukin-18 Receptor beta SubunitMotor Neurons3' Untranslated RegionsIL18RAP protein, humanInterleukin-18 Receptor beta Subunit
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