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To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strategy, we performed gene-burden analyses trained with established ALS genes and identified a significant association between loss-of-function (LOF) NEK1 variants and FALS risk. Independently, autozygosity mapping for an isolated community in the Netherlands identified a NEK1 p.Arg261His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261His (10,589 samples analyzed) and NEK1 LOF variants (3,362 samples analyzed). In total, we observed NEK1 risk variants in nearly 3% of ALS cases. NEK1 has been linked to several cellular functions, including cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity. Our results provide new and important insights into ALS etiopathogenesis and genetic etiology.

Original publication

DOI

10.1038/ng.3626

Type

Journal article

Journal

Nat Genet

Publication Date

09/2016

Volume

48

Pages

1037 - 1042

Keywords

Amyotrophic Lateral Sclerosis, Case-Control Studies, Cohort Studies, Exome, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Mutation, NIMA-Related Kinase 1, Netherlands