Abstract
BackgroundAmyotrophic 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.MethodsFirst, 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.FindingsWe 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.InterpretationOur 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.FundingWe 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).
Highlights
Research in contextEvidence before this studyThe role of physical activity as a risk factor for Amyotrophic lateral sclerosis (ALS) was evaluated in a systematic review of 26 studies performed by Lacorte et al in 2016
A single recent study used linkage disequilibrium score regression and Mendelian randomisation to test for a causal relationship between ALS and a number of UK biobank questionnaire items including participation in light DIY, walking for pleasure and moderate activity duration, but this study did not address the relationship between ALS and physical exercise which is both frequent and strenuous
Our previous work has indicated that leisure-time strenuous activity may be linked to risk of ALS [9]; this is captured by a ‘strenuous sport and other exercise’ (SSOE) genome-wide association study (GWAS) (Methods) [21]
Summary
The role of physical activity as a risk factor for ALS was evaluated in a systematic review of 26 studies performed by Lacorte et al in 2016. Our results indicate that participation in frequent and strenuous leisure time physical activity is a risk factor for ALS, in the context of certain risk genotypes This could explain some of the controversy in previous studies which have largely neglected genetic heterogeneity within ALS patients. In ALS it is the motor neurons supplying type IIb muscle fibres responsible for anaerobic burst activity which are most vulnerable to the disease process [16,17] On this basis we propose that ALS may be associated with vigorous exercise and this hypothesis is consistent with several previous studies [9,18].
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