Physical exercise is a risk factor for amyotrophic lateral sclerosis: Convergent evidence from mendelian randomisation, transcriptomics and risk genotypes

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 We dissected the exercise-ALS relationship in a series of two-sample Mendelian randomisation (MR) experiments. We then we tested for enrichment of ALS genetic risk within exercise-associated transcriptome changes. Finally, we applied a validated physical activity (PA) questionnaire in a small cohort of genetically selected ALS patients. Findings We present MR evidence supporting a causal relationship between genetic liability to strenuous leisure-time exercise and ALS (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 PA for C9ORF72 -ALS (linear regression, t=-2.28, p=0.036) but not for non -C9ORF72 -ALS. Moreover, compared to non- C9ORF72 -ALS patients and neurologically normal controls, C9ORF72 -ALS cases reported the highest minimum average PA (20.9kJ/kg/day) consistent with an exercise threshold for penetrance. 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, and P30DK116074, UM1HG009442). RESEARCH IN CONTEXT Evidence before this study The role of physical activity (PA) as a risk factor for ALS was evaluated in a systematic review of 26 studies performed by Lacorte et al . in 2016. The authors concluded that there was insufficient evidence to draw a firm conclusion. The authors highlighted limitations of previous studies relating to heterogeneous classification of PA and ALS. They noted that none of the published literature achieved the highest quality rating in the Newcastle Ottawa Scale, which they attribute to methodological challenges posed by the rarity and severity of the disease. Failure to address genetic subtypes of ALS was proposed as a shortcoming in the studies surveyed. To identify more recent publications, we conducted a literature search using the PubMed database for articles published between 01/01/2015 - 11/11/2020. The search terms used were (“Amyotrophic lateral sclerosis”[Title/Abstract] OR “motor neuron disease”[Title/Abstract] OR MND[Title/Abstract] OR ALS[Title/Abstract]) AND (PA[Title/Abstract] OR exercise[Title/Abstract] OR “physical activity”[Title/Abstract] OR sport[Title/Abstract]). This search strategy yielded 182 results and we filtered for original, observational, human-subject studies but we excluded case series with <10 participants and case reports. This process identified 12 further relevant publications which report opposite conclusions without significantly addressing the methodological issues highlighted above. 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 strenuous, frequent physical exercise. Added value of this study In the present study, we have exploited the methodological advantages of mendelian randomisation (MR) to counter bias, together with a tailored approach to PA exposure aimed at isolating strenuous, frequent physical exercise. We achieved this by selecting and combining UK biobank questionnaire items. In contrast to previous studies, we have addressed the gene-environment interaction by measuring the effect of exercise on expression of ALS risk genes. Furthermore, we have considered in detail the relationship between PA and the most frequent genetic risk factor for ALS: hexanucleotide (G4C2) repeat expansion of C9ORF72 . Our data suggests that genetic liability to leisure time physical activity is a risk factor for ALS and C9ORF72 -ALS in particular. In addition, we offer evidence that a number of known ALS-associated genetic variants are functionally linked to the physiological response to exercise. Implications of all the available evidence Our results indicate that participation in leisure time physical activity is a risk factor for ALS particularly 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. Our results form a platform for future research to explore the interaction between specific genotypes and exercise-induced ALS in a prospective manner with larger numbers, and in selected pedigrees. Ultimately this could lead to the design of personalised medicine including lifestyle advice regarding physical activity, to patients with ALS and their family members.

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