Common and rare variant association analyses in Amyotrophic Lateral Sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci. When combined with 8,953 whole-genome sequenced individuals (6,538 patients, 2,415 controls) and a large cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Of the environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.

W.Rheenen, et al. Nature Genetics (2021)

Download link includes:

  • GWAS summary statistics, cross-ancestry meta-analysis
  • GWAS summary statistics, European-ancestry meta-analysis
  • Rare-variant burden analysis summary statistics
  • eQTL SMR summary statistics for eQTLGen and MetaBrain