The Effect of SMN Gene Dosage on ALS Risk and Disease Severity
Project MinE Sequencing Consortium
(2021) Annals of Neurology, volume 89, issue 4, pp. 686 - 697
(Article)
Abstract
OBJECTIVE: The role of the survival of motor neuron (SMN) gene in amyotrophic lateral sclerosis (ALS) is unclear, with several conflicting reports. A decisive result on this topic is needed, given that treatment options are available now for SMN deficiency. METHODS: In this largest multicenter case control study to evaluate
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the effect of SMN1 and SMN2 copy numbers in ALS, we used whole genome sequencing data from Project MinE data freeze 2. SMN copy numbers of 6,375 patients with ALS and 2,412 controls were called from whole genome sequencing data, and the reliability of the calls was tested with multiplex ligation-dependent probe amplification data. RESULTS: The copy number distribution of SMN1 and SMN2 between cases and controls did not show any statistical differences (binomial multivariate logistic regression SMN1 p = 0.54 and SMN2 p = 0.49). In addition, the copy number of SMN did not associate with patient survival (Royston-Parmar; SMN1 p = 0.78 and SMN2 p = 0.23) or age at onset (Royston-Parmar; SMN1 p = 0.75 and SMN2 p = 0.63). INTERPRETATION: In our well-powered study, there was no association of SMN1 or SMN2 copy numbers with the risk of ALS or ALS disease severity. This suggests that changing SMN protein levels in the physiological range may not modify ALS disease course. This is an important finding in the light of emerging therapies targeted at SMN deficiencies. ANN NEUROL 2021;89:686-697.
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Keywords: Amyotrophic Lateral Sclerosis/genetics, Case-Control Studies, Cohort Studies, Female, Gene Dosage, Humans, Male, Reproducibility of Results, Risk Factors, Severity of Illness Index, Survival of Motor Neuron 1 Protein/genetics, Survival of Motor Neuron 2 Protein/genetics, Whole Genome Sequencing, Clinical Neurology, Neurology, Research Support, Non-U.S. Gov't, Journal Article, Research Support, N.I.H., Extramural
ISSN: 0364-5134
Publisher: John Wiley and Sons Inc.
Note: Funding Information: The authors thank the patients, their families, and healthy controls for their participation in this project. Samples were sequenced as part of Project MinE. Project MinE Belgium was supported by a grant from IWT (no. 140935), FWO‐Vlaanderen (G0B2819N), 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 (ERN‐NMD). 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). This study was supported by the ALS Foundation Netherlands. 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. This is in part an EU Joint Programme ‐ Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organizations under the aegis of JPND ‐ www.jpnd.eu (United Kingdom, Medical Research Council (MR/L501529/1; MR/R024804/1, the Netherlands, ZONMW, grant no. 733051071, BRAIN‐MEND), and through the Motor Neurone Disease Association. This study represents independent research part funded by the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre. 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. Funding was provided to J.E.L. by the NIH/NINDS (R01NS073873) and the ALS Association. V.S. receives or has received research supports from the Italian Ministry of Health (Grant RF‐201302355764), Fondazione Italiana di Ricerca per la SLA – AriSLA (Grant Exomefals and Novals), Fondazione Regionale per la Ricerca Biomedica Regione Lombardia (Project no. 2015–0023), and E‐RARE JTC (Project Repetomics). R.McL. is supported by Science Foundation Ireland (17/CDA/4737). Publisher Copyright: © 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
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