Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis
Al Khleifat, Ahmad; Iacoangeli, Alfredo; van Vugt, Joke J F A; Bowles, Harry; Moisse, Matthieu; Zwamborn, Ramona A J; van der Spek, Rick A A; Shatunov, Aleksey; Cooper-Knock, Johnathan; Topp, Simon; Byrne, Ross; Gellera, Cinzia; López, Victoria; Jones, Ashley R; Opie-Martin, Sarah; Vural, Atay; Campos, Yolanda; van Rheenen, Wouter; Kenna, Brendan; Van Eijk, Kristel R; Kenna, Kevin; Weber, Markus; Smith, Bradley; Fogh, Isabella; Silani, Vincenzo; Morrison, Karen E; Dobson, Richard; van Es, Michael A; McLaughlin, Russell L; Vourc'h, Patrick; Chio, Adriano; Corcia, Philippe; de Carvalho, Mamede; Gotkine, Marc; Panades, Monica P; Mora, Jesus S; Shaw, Pamela J; Landers, John E; Glass, Jonathan D; Shaw, Christopher E; Basak, Nazli; Hardiman, Orla; Robberecht, Wim; Van Damme, Philip; van den Berg, Leonard H; Veldink, Jan H; Al-Chalabi, Ammar
(2022) npj Genomic Medicine, volume 7, issue 1, pp. 1 - 8
(Article)
Abstract
There is a strong genetic contribution to Amyotrophic lateral sclerosis (ALS) risk, with heritability estimates of up to 60%. Both Mendelian and small effect variants have been identified, but in common with other conditions, such variants only explain a little of the heritability. Genomic structural variation might account for some
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of this otherwise unexplained heritability. We therefore investigated association between structural variation in a set of 25 ALS genes, and ALS risk and phenotype. As expected, the repeat expansion in the C9orf72 gene was identified as associated with ALS. Two other ALS-associated structural variants were identified: inversion in the VCP gene and insertion in the ERBB4 gene. All three variants were associated both with increased risk of ALS and specific phenotypic patterns of disease expression. More than 70% of people with respiratory onset ALS harboured ERBB4 insertion compared with 25% of the general population, suggesting respiratory onset ALS may be a distinct genetic subtype.
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Keywords: Molecular Biology, Genetics, Genetics(clinical)
ISSN: 2056-7944
Publisher: Nature Publishing Group
Note: Funding Information: 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 thank people with MND and their families for their participation in this project. 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. This research was funded in whole, or in part, by the Wellcome Trust [Grant number]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. The authors acknowledge use of the research computing facility at King’s College London, Rosalind (https://rosalind.kcl.ac.uk), which is delivered in partnership with the National Institute for Health Research (NIHR) Biomedical Research Centres at South London & Maudsley and Guy’s & St. Thomas’ NHS Foundation Trusts, and part-funded by capital equipment grants from the Maudsley Charity (award 980) and Guy’s & St. Thomas’ Charity (TR130505). The views expressed are those of the author (s) and not necessarily those of the NHS, the NIHR, King’s College London, or the Department of Health and Social Care. National. The authors acknowledge Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The authors acknowledge Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome Trust. A.A.K. is funded by The Motor Neurone Disease Association (MNDA), NIHR Maudsley Biomedical Research Centre and and ALS Association Milton Safenowitz Research Fellowship. This project was funded by the MND Association and the Wellcome Trust. This is an EU Joint Programme-Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organisations under the aegis of JPND - www.jpnd.eu (United Kingdom, Medical Research Council (MR/L501529/1 and MR/R024804/1) and Economic and Social Research Council (ES/L008238/1)). A.A.C. is an NIHR Senior Investigator. C.E.S. and A.A.C. receive salary support from the National Institute for Health Research (NIHR) Dementia Biomedical Research Unit at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The work leading up to this publication was funded by the European Community’s Health Seventh Framework Program (FP7/2007–2013; grant agreement number 259867) and Horizon 2020 Program (H2020-PHC-2014-two-stage; grant agreement number 633413). This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 772376 - EScORIAL. The collaboration project is co-funded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships. Project MinE Belgium was supported by a grant from IWT, the Belgian ALS Liga and a grant from Opening the Future Fund (KU Leuven). PVD 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”. R.L.McL. is supported by Science Foundation Ireland (17/CDA/4737). MinE USA is funded by the US ALS Association. We thank the patients and families from the Emory ALS Clinic participating in this research. Funding was provided by US National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) (R01NS073873, J.E.L.) and the American ALS Association (J.E.L.). Funding Information: A.A.C. is a consultant for Mitsubishi-Tanabe Pharma, GSK, and Chronos Therapeutics, and chief investigator for clinical trials for Cytokinetics and OrionPharma. J.H.V. is a consultant for Biogen. L.H.V.D.B. reports grants from Netherlands ALS Foundation, grants from The Netherlands Organization for Health Research and Development (Vici scheme), grants from The European Community’s Health Seventh Framework Programme (grant agreement no. 259867 (EuroMOTOR)), grants from The Netherlands Organization for Health Research and Development)the STRENGTH project, funded through the EU Joint Programme – Neurodegenerative Disease Research, JPND), during the conduct of the study; personal fees from Calico, personal fees from Cytokinetics, grants and personal fees from Takeda, non-financial support from Orion, non-financial support from Orphazyme, outside the submitted work. CES reports grants from Avexis, grants from Eli Lilly, grants from Chronos Therapeutics, grants from Vertex Pharmaceuticals, during the conduct of the study; grants from QurAlis, grants from Chronos Therapeutics, grants from Biogen, outside the submitted work. A.A.K., O.H., M.P.P., J.S.M., P.J.S., J.E.L., C.E.S., N.B., O.H., W.R., P.V.D., N.B., K.K., B.K., H.B., and L.H.V.B. declare no competing interests. Publisher Copyright: © 2022, The Author(s).
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