NEK1 variants confer susceptibility to amyotrophic lateral sclerosis.
Kevin P KennaPerry T C van DoormaalAnnelot M DekkerNicola TicozziBrendan J KennaFrank P DiekstraWouter van RheenenKristel R van EijkAshley R JonesPamela KeagleAleksey ShatunovWilliam SprovieroBradley N SmithMichael A van EsSimon D ToppAoife KennaJack W MillerClaudia FalliniCinzia TilocaRussell L McLaughlinCaroline VanceClaire TroakesClaudia ColombritaGabriele MoraAndrea CalvoFederico VerdeSafa Al-SarrajAndrew KingDaniela CaliniJacqueline de BellerocheFrank BaasAnneke J van der KooiMarianne de VisserAnneloor L M A Ten AsbroekPeter C SappDiane McKenna-YasekMeraida PolakSeneshaw AsressJosé Luis Muñoz-BlancoTim M StromThomas MeitingerKaren E Morrisonnull nullGiuseppe LauriaKelly Louise WilliamsP Nigel LeighGarth A NicholsonIan P BlairClaire S LeblondPatrick A DionGuy A RouleauHardev PallPamela J ShawMatthew C KiernanKevin TalbotFranco TaroniKevin B BoylanMarka Van BlitterswijkRosa RademakersJesús Esteban-PérezAlberto García-RedondoPhillip Van DammeWim RobberechtAdriano ChioCinzia GelleraCarsten DrepperMichael SendtnerAntonia RattiJonathan D GlassJesús S MoraNazli A BasakOrla HardimanAlbert C LudolphPeter M AndersenJochen H WeishauptRobert H BrownAmmar Al-ChalabiVincenzo SilaniChristopher E ShawLeonard H van den BergJan H VeldinkJohn E LandersPublished in: Nature genetics (2016)
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.