NEK1 variants confer susceptibility to amyotrophic lateral sclerosis

To identify genetic factors contributing to amyotrophic lateral  sclerosis (ALS), we conducted whole-exome analyses of  ,022 index familial ALS (FALS) cases and 7,35 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.Arg26His  variant as a candidate risk factor. Replication analyses of  sporadic ALS (SALS) cases and independent control cohorts  confirmed significant disease association for both p.Arg26His  (0,589 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.