To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole genome- sequenced ALS patients and matched controls (N = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine mapped a novel locus on chromosome 21 and identified C21orf2 as an ALS risk gene. In addition, we identified MOBP and SCFD1 as novel associated risk loci. We established evidence for ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low frequency (1 to 10%) variants. This study motivates the interrogation of larger sample sizes with full genome coverage to identify rare causal variants that underpin ALS risk.

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