Julian, T.H. orcid.org/0000-0002-5488-5620, Glascow, N., Barry, A.D.F. et al. (8 more authors) (2021) Physical exercise is a risk factor for amyotrophic lateral sclerosis: Convergent evidence from Mendelian randomisation, transcriptomics and risk genotypes. EBioMedicine, 68. 103397. ISSN 2352-3964
Abstract
Background
Amyotrophic lateral sclerosis (ALS) is a universally fatal neurodegenerative disease. ALS is determined by gene-environment interactions and improved understanding of these interactions may lead to effective personalised medicine. The role of physical exercise in the development of ALS is currently controversial.
Methods
First, we dissected the exercise-ALS relationship in a series of two-sample Mendelian randomisation (MR) experiments. Next we tested for enrichment of ALS genetic risk within exercise-associated transcriptome changes. Finally, we applied a validated physical activity questionnaire in a small cohort of genetically selected ALS patients.
Findings
We present MR evidence supporting a causal relationship between genetic liability to frequent and strenuous leisure-time exercise and ALS using a liberal instrument (multiplicative random effects IVW, p=0.01). Transcriptomic analysis revealed that genes with altered expression in response to acute exercise are enriched with known ALS risk genes (permutation test, p=0.013) including C9ORF72, and with ALS-associated rare variants of uncertain significance. Questionnaire evidence revealed that age of onset is inversely proportional to historical physical activity for C9ORF72-ALS (Cox proportional hazards model, Wald test p=0.007, likelihood ratio test p=0.01, concordance=74%) but not for non-C9ORF72-ALS. Variability in average physical activity was lower in C9ORF72-ALS compared to both non-C9ORF72-ALS (F-test, p=0.002) and neurologically normal controls (F-test, p=0.049) which is consistent with a homogeneous effect of physical activity in all C9ORF72-ALS patients.
Interpretation
Our MR approach suggests a positive causal relationship between ALS and physical exercise. Exercise is likely to cause motor neuron injury only in patients with a risk-genotype. Consistent with this we have shown that ALS risk genes are activated in response to exercise. In particular, we propose that G4C2-repeat expansion of C9ORF72 predisposes to exercise-induced ALS.
Funding
We acknowledge support from the Wellcome Trust (JCK, 216596/Z/19/Z), NIHR (PJS, NF-SI-0617-10077; IS-BRC-1215-20017) and NIH (MPS, CEGS 5P50HG00773504, 1P50HL083800, 1R01HL101388, 1R01-HL122939, S10OD025212, P30DK116074, and UM1HG009442).
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) |
Keywords: | Amyotrophic lateral sclerosis; Mendelian randomisation; Physical exercise; C9ORF72 |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals |
Funding Information: | Funder Grant number WELLCOME TRUST (THE) 216596/Z/19/Z National Institute for Health Research NIHRDH-IS-BRC-1215-20017 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 18 Jun 2021 16:18 |
Last Modified: | 18 Jun 2021 16:18 |
Status: | Published |
Publisher: | Elsevier BV |
Refereed: | Yes |
Identification Number: | 10.1016/j.ebiom.2021.103397 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:174856 |
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Filename: Julian et al 2021 Physical Exercise is a risk factor for ALS.pdf
Licence: CC-BY 4.0