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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 patients with ALS 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 new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of 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 variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.

Original publication

DOI

10.1038/ng.3622

Type

Journal article

Journal

Nat genet

Publication Date

09/2016

Volume

48

Pages

1043 - 1048

Keywords

Amyotrophic Lateral Sclerosis, Case-Control Studies, Cohort Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Munc18 Proteins, Mutation, Myelin Proteins, Netherlands, Proteins