MR evidence supported a relationship between genetic liability to frequent strenuous leisure-time exercise and ALS. Transcriptomic analysis showed that genes altered in response to acute exercise are enriched with known ALS risk genes. A positive relationship found between age of onset of G4C2-repeat expansion C9orf72-ALS and strenuous, leisure-time exercise. Here, C9orf72 is linked to amyotrophic lateral sclerosis.