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

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Whole-genome sequencing reveals that variants in the Interleukin 18 Receptor Accessory Protein 3'UTR protect against ALS
 
Project MinE ALS Sequencing Consortium
(2022) Nature Neuroscience, volume 25, issue 4, pp. 433 - 445
(Article)
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 ... read more
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Keywords: 3' Untranslated Regions/genetics, Amyotrophic Lateral Sclerosis/genetics, Humans, Induced Pluripotent Stem Cells/metabolism, Interleukin-18 Receptor beta Subunit/genetics, Motor Neurons/metabolism, Journal Article
DOI: https://doi.org/10.1038/s41593-022-01040-6
ISSN: 1097-6256
Publisher: Nature Publishing Group
Note: Funding Information: We gratefully acknowledge the contributions of all participants and the investigators who provided biological samples and data for the Project Mine ALS sequencing consortium, the NYGC ALS Consortium, the gnomAD and TOPMed of the NHLBI ( https://www.nhlbiwgs.org/topmed-banner-authorship ). We thank M. Ward (NINDS, NIH) for sharing human inducible iLMN cells. Samples used in this research were in part obtained from the UK National DNA Bank for MND Research, funded by the MND Association and the Wellcome Trust. We acknowledge sample management undertaken by Biobanking Solutions funded by the Medical Research Council at the Centre for Integrated Genomic Medical Research, University of Manchester. We would like to thank the NINDS Biorepository at Coriell Institute for iPSC cell lines used in this study. We thank B. Oldak and J. Hanna for microglia differentiation protocols, N. Kozer and H. Barr for assistance with live-cell imaging, A. Savidor and Y. Levin for mass spectrometry and M. Shmueli, Y. Merbl and R. Rotkof for advice and protocols. We thank LSE for language and scientific editing. Some illustrations were created with BioRender. The Hornstein lab is supported by friends of S. Brenner. E.H. is Head of Andi and Larry Wolfe Center for Research on Neuroimmunology and Neuromodulation and incumbent of Ira & Gail Mondry Professorial chair. This work is funded by Legacy Heritage Fund (828/17), Bruno and Ilse Frick Foundation for Research on ALS, the RADALA Foundation for ALS research, Teva Pharmaceutical Industries., Ltd., as part of the Israeli National Network of Excellence in Neuroscience (NNE) and Minna-James-Heineman Stiftung through Minerva, the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement number 617351, Israel Science Foundation (135/16, 3497/21); Target ALS 118945, the Minerva Foundation, with funding from the Federal German Ministry for Education and Research, the ALS-Therapy Alliance, AFM Telethon (20576 to E.H.), Motor Neuron Disease Association (UK), The Thierry Latran Foundation for ALS research, ERA-Net for Research Programmes on Rare Diseases (FP7), via the Israel Ministry of Health. A. Alfred Taubman through IsrALS, Yeda-Sela, Yeda-CEO, Israel Ministry of Trade and Industry, Y. Leon Benoziyo Institute for Molecular Medicine, Kekst Family Institute for Medical Genetics, David and Fela Shapell Family Center for Genetic Disorders Research, Crown Human Genome Center, Nathan, Shirley, Philip and Charlene Vener New Scientist Fund, Julius and Ray Charlestein Foundation, Fraida Foundation, Wolfson Family Charitable Trust, Adelis Foundation, Merck (UK), Maria Halphen, Estates of Fannie Sherr, Lola Asseof, Lilly Fulop, Andi and Larry Wolfe Center for Research on Neuroimmunology and Neuromodulation and Benoziyo center for Neurological diseases, Weizmann—Brazil Center for Research on Neurodegeneration at The Weizmann Institute of Science, Redhill Foundation—Sam and Jean Rothberg Charitable Trust, Edward and Janie Moravitz, the Israeli Council for Higher Education via the Weizmann Data Science Research Center and a research grant from the Estate of Tully and Michele Plesser and M. Judith Ruth Institute for Preclinical Brain Research. A.A.-C. received funding from Neurodegenerative Disease Research (JPND), Medical Research Council (MR/L501529/1, STRENGTH, MR/R024804/1, BRAIN-MEND), Economic and Social Research Council (ES/L008238/1, ALS-CarE), MND Association, National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement number 772376, EScORIAL). The collaboration project is cofunded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences & Health to stimulate public–private partnerships. This study was supported by the ALS Foundation Netherlands. For P.V.D., Project MinE Belgium was supported by a grant from IWT (number 140935), the ALS Liga België, the National Lottery of Belgium and the KU Leuven Opening the Future Fund. P.V.D. holds a senior clinical investigatorship of FWO-Vlaanderen and is supported by E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders, the ALS Liga België and the KU Leuven funds ‘Een Hart voor ALS’, ‘Laeversfonds voor ALS Onderzoek’ and the ‘Valéry Perrier Race against ALS Fund’. Several authors of this publication are members of the European Reference Network for Rare Neuromuscular Diseases. P.J.S. received funding from the Medical Research Council, MND Association, NIHR Senior Investigator Award, NIHR Sheffield Biomedical Research Centre and NIHR Sheffield Clinical Research Facility. P.M.A. received funding from the Knut and Alice Wallenberg Foundation, the Swedish Brain Foundation, the Swedish Science Council and the Ulla-Carin Lindquist Foundation. H.P.P. and sequencing activities at NYGC were supported by the ALS Association and The Tow Foundation. C.E. was supported by a scholarship from Teva Pharmaceutical Industries, Ltd., as part of the NNE. S.M.K.F. is supported by the ALS Canada Tim E. Noël Postdoctoral Fellowship. R.H.B.J. was funded by the ALS Association, ALS Finding a Cure, Angel Fund, ALS-One, Cellucci Fund and NIH grants (R01 NS104022, R01 NS073873 and NS111990-01 to R.H.B.J.). J.K.I. is a New York Stem Cell Foundation-Robertson Investigator. N.S.Y. was supported by the Israeli Council for Higher Education via the Weizmann Data Science Research Center, by a research grant from the Estate of Tully and Michele Plesser and by Maccabim Foundation. Work in the J.K.I. lab was supported by NIH grant R01NS097850, U.S. Department of Defense grant W81XWH-19-PRARP-CSRA and grants from the Tau Consortium, the New York Stem Cell Foundation, the ALS Association and the John Douglas French Alzheimer’s Foundation. R.L.McL. received funding from the Science Foundation Ireland (17/CDA/4737), and A.N.B. received funding from the Suna and Inan Kirac Foundation. J.E.L. received funding from the National Institute of Health/NINDS (R01 NS073873). 3 Funding Information: We gratefully acknowledge the contributions of all participants and the investigators who provided biological samples and data for the Project Mine ALS sequencing consortium, the NYGC ALS Consortium, the gnomAD and TOPMed of the NHLBI (https://www.nhlbiwgs.org/topmed-banner-authorship). We thank M. Ward (NINDS, NIH) for sharing human inducible i3 LMN cells. Samples used in this research were in part obtained from the UK National DNA Bank for MND Research, funded by the MND Association and the Wellcome Trust. We acknowledge sample management undertaken by Biobanking Solutions funded by the Medical Research Council at the Centre for Integrated Genomic Medical Research, University of Manchester. We would like to thank the NINDS Biorepository at Coriell Institute for iPSC cell lines used in this study. We thank B. Oldak and J. Hanna for microglia differentiation protocols, N. Kozer and H. Barr for assistance with live-cell imaging, A. Savidor and Y. Levin for mass spectrometry and M. Shmueli, Y. Merbl and R. Rotkof for advice and protocols. We thank LSE for language and scientific editing. Some illustrations were created with BioRender. The Hornstein lab is supported by friends of S. Brenner. E.H. is Head of Andi and Larry Wolfe Center for Research on Neuroimmunology and Neuromodulation and incumbent of Ira & Gail Mondry Professorial chair. This work is funded by Legacy Heritage Fund (828/17), Bruno and Ilse Frick Foundation for Research on ALS, the RADALA Foundation for ALS research, Teva Pharmaceutical Industries., Ltd., as part of the Israeli National Network of Excellence in Neuroscience (NNE) and Minna-James-Heineman Stiftung through Minerva, the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement number 617351, Israel Science Foundation (135/16, 3497/21); Target ALS 118945, the Minerva Foundation, with funding from the Federal German Ministry for Education and Research, the ALS-Therapy Alliance, AFM Telethon (20576 to E.H.), Motor Neuron Disease Association (UK), The Thierry Latran Foundation for ALS research, ERA-Net for Research Programmes on Rare Diseases (FP7), via the Israel Ministry of Health. A. Alfred Taubman through IsrALS, Yeda-Sela, Yeda-CEO, Israel Ministry of Trade and Industry, Y. Leon Benoziyo Institute for Molecular Medicine, Kekst Family Institute for Medical Genetics, David and Fela Shapell Family Center for Genetic Disorders Research, Crown Human Genome Center, Nathan, Shirley, Philip and Charlene Vener New Scientist Fund, Julius and Ray Charlestein Foundation, Fraida Foundation, Wolfson Family Charitable Trust, Adelis Foundation, Merck (UK), Maria Halphen, Estates of Fannie Sherr, Lola Asseof, Lilly Fulop, Andi and Larry Wolfe Center for Research on Neuroimmunology and Neuromodulation and Benoziyo center for Neurological diseases, Weizmann—Brazil Center for Research on Neurodegeneration at The Weizmann Institute of Science, Redhill Foundation—Sam and Jean Rothberg Charitable Trust, Edward and Janie Moravitz, the Israeli Council for Higher Education via the Weizmann Data Science Research Center and a research grant from the Estate of Tully and Michele Plesser and M. Judith Ruth Institute for Preclinical Brain Research. A.A.-C. received funding from Neurodegenerative Disease Research (JPND), Medical Research Council (MR/L501529/1, STRENGTH, MR/R024804/1, BRAIN-MEND), Economic and Social Research Council (ES/L008238/1, ALS-CarE), MND Association, National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement number 772376, EScORIAL). The collaboration project is cofunded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences & Health to stimulate public–private partnerships. This study was supported by the ALS Foundation Netherlands. For P.V.D., Project MinE Belgium was supported by a grant from IWT (number 140935), the ALS Liga België, the National Lottery of Belgium and the KU Leuven Opening the Future Fund. P.V.D. holds a senior clinical investigatorship of FWO-Vlaanderen and is supported by E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders, the ALS Liga België and the KU Leuven funds ‘Een Hart voor ALS’, ‘Laeversfonds voor ALS Onderzoek’ and the ‘Valéry Perrier Race against ALS Fund’. Several authors of this publication are members of the European Reference Network for Rare Neuromuscular Diseases. P.J.S. received funding from the Medical Research Council, MND Association, NIHR Senior Investigator Award, NIHR Sheffield Biomedical Research Centre and NIHR Sheffield Clinical Research Facility. P.M.A. received funding from the Knut and Alice Wallenberg Foundation, the Swedish Brain Foundation, the Swedish Science Council and the Ulla-Carin Lindquist Foundation. H.P.P. and sequencing activities at NYGC were supported by the ALS Association and The Tow Foundation. C.E. was supported by a scholarship from Teva Pharmaceutical Industries, Ltd., as part of the NNE. S.M.K.F. is supported by the ALS Canada Tim E. Noël Postdoctoral Fellowship. R.H.B.J. was funded by the ALS Association, ALS Finding a Cure, Angel Fund, ALS-One, Cellucci Fund and NIH grants (R01 NS104022, R01 NS073873 and NS111990-01 to R.H.B.J.). J.K.I. is a New York Stem Cell Foundation-Robertson Investigator. N.S.Y. was supported by the Israeli Council for Higher Education via the Weizmann Data Science Research Center, by a research grant from the Estate of Tully and Michele Plesser and by Maccabim Foundation. Work in the J.K.I. lab was supported by NIH grant R01NS097850, U.S. Department of Defense grant W81XWH-19-PRARP-CSRA and grants from the Tau Consortium, the New York Stem Cell Foundation, the ALS Association and the John Douglas French Alzheimer’s Foundation. R.L.McL. received funding from the Science Foundation Ireland (17/CDA/4737), and A.N.B. received funding from the Suna and Inan Kirac Foundation. J.E.L. received funding from the National Institute of Health/NINDS (R01 NS073873). Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
(Peer reviewed)