NEK1 variants confer susceptibility to amyotrophic lateral sclerosis

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.

[1]  M. Schemper,et al.  A solution to the problem of separation in logistic regression , 2002, Statistics in medicine.

[2]  M. Pericak-Vance,et al.  A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10). , 2002, American journal of human genetics.

[3]  J. Kobarg,et al.  Identification of proteins that interact with the central coiled-coil region of the human protein kinase NEK1. , 2003, Biochemistry.

[4]  Shin J. Oh,et al.  Mutant dynactin in motor neuron disease , 2003, Nature Genetics.

[5]  S. Batzoglou,et al.  Distribution and intensity of constraint in mammalian genomic sequence. , 2005, Genome research.

[6]  L. Quarmby,et al.  The NIMA-family kinase, Nek1 affects the stability of centrosomes and ciliogenesis , 2008, BMC Cell Biology.

[7]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[8]  Y. Altschuler,et al.  The mammalian Nek1 kinase is involved in primary cilium formation , 2008, FEBS letters.

[9]  Peter Nürnberg,et al.  HomozygosityMapper—an interactive approach to homozygosity mapping , 2009, Nucleic Acids Res..

[10]  W. Craigen,et al.  Nek1 regulates cell death and mitochondrial membrane permeability through phosphorylation of VDAC1 , 2009, Cell cycle.

[11]  Xiaohui Xie,et al.  Identifying novel constrained elements by exploiting biased substitution patterns , 2009, Bioinform..

[12]  J. Milbrandt,et al.  The NIMA-family kinase Nek3 regulates microtubule acetylation in neurons , 2009, Journal of Cell Science.

[13]  Justin C. Fay,et al.  Identification of deleterious mutations within three human genomes. , 2009, Genome research.

[14]  S. Henikoff,et al.  Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm , 2009, Nature Protocols.

[15]  J. Gleeson,et al.  The role of primary cilia in neuronal function , 2010, Neurobiology of Disease.

[16]  Jana Marie Schwarz,et al.  MutationTaster evaluates disease-causing potential of sequence alterations , 2010, Nature Methods.

[17]  Serafim Batzoglou,et al.  Identifying a High Fraction of the Human Genome to be under Selective Constraint Using GERP++ , 2010, PLoS Comput. Biol..

[18]  Josyf Mychaleckyj,et al.  Robust relationship inference in genome-wide association studies , 2010, Bioinform..

[19]  Yun Li,et al.  METAL: fast and efficient meta-analysis of genomewide association scans , 2010, Bioinform..

[20]  Emily H Turner,et al.  Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome , 2010, Nature Genetics.

[21]  D. Moura,et al.  Nek1 silencing slows down DNA repair and blocks DNA damage-induced cell cycle arrest. , 2010, Mutagenesis.

[22]  M. DePristo,et al.  A framework for variation discovery and genotyping using next-generation DNA sequencing data , 2011, Nature Genetics.

[23]  Christian Gilissen,et al.  Unlocking Mendelian disease using exome sequencing , 2011, Genome Biology.

[24]  C. Sander,et al.  Predicting the functional impact of protein mutations: application to cancer genomics , 2011, Nucleic acids research.

[25]  A. Ekici,et al.  NEK1 mutations cause short-rib polydactyly syndrome type majewski. , 2011, American journal of human genetics.

[26]  P. Visscher,et al.  GCTA: a tool for genome-wide complex trait analysis. , 2011, American journal of human genetics.

[27]  J. Turnbull,et al.  Adenylyl Cyclase type 3, a marker of primary cilia, is reduced in primary cell culture and in lumbar spinal cord in situ in G93A SOD1 mice , 2011, BMC Neuroscience.

[28]  J. Miller,et al.  Predicting the Functional Effect of Amino Acid Substitutions and Indels , 2012, PloS one.

[29]  P. Rossini,et al.  Contribution of major amyotrophic lateral sclerosis genes to the etiology of sporadic disease , 2012, Neurology.

[30]  Kenny Q. Ye,et al.  An integrated map of genetic variation from 1,092 human genomes , 2012, Nature.

[31]  Pablo Cingolani,et al.  © 2012 Landes Bioscience. Do not distribute. , 2022 .

[32]  A. Chiò,et al.  Extensive genetics of ALS , 2012, Neurology.

[33]  Tom R. Gaunt,et al.  Predicting the Functional, Molecular, and Phenotypic Consequences of Amino Acid Substitutions using Hidden Markov Models , 2012, Human mutation.

[34]  Lance Lee.  Riding the wave of ependymal cilia: Genetic susceptibility to hydrocephalus in primary ciliary dyskinesia , 2013, Journal of neuroscience research.

[35]  Semyon Kruglyak,et al.  Isaac: ultra-fast whole-genome secondary analysis on Illumina sequencing platforms , 2013, Bioinform..

[36]  D. Morris,et al.  Delineating the genetic heterogeneity of ALS using targeted high-throughput sequencing , 2013, Journal of Medical Genetics.

[37]  I. Adzhubei,et al.  Predicting Functional Effect of Human Missense Mutations Using PolyPhen‐2 , 2013, Current protocols in human genetics.

[38]  Y. Shav-Tal,et al.  Nek7 kinase accelerates microtubule dynamic instability. , 2013, Biochimica et biophysica acta.

[39]  Masato Kimura,et al.  NCBI’s Database of Genotypes and Phenotypes: dbGaP , 2013, Nucleic Acids Res..

[40]  L. Tsai,et al.  DNA Damage and Its Links to Neurodegeneration , 2014, Neuron.

[41]  D. A. Bosco,et al.  Functions of FUS/TLS From DNA Repair to Stress Response: Implications for ALS , 2014, ASN neuro.

[42]  M. Schatz,et al.  Reducing INDEL calling errors in whole genome and exome sequencing data , 2014, Genome Medicine.

[43]  J. Shendure,et al.  A general framework for estimating the relative pathogenicity of human genetic variants , 2014, Nature Genetics.

[44]  Adriano Chiò,et al.  State of play in amyotrophic lateral sclerosis genetics , 2013, Nature Neuroscience.

[45]  Eric Boerwinkle,et al.  In silico prediction of splice-altering single nucleotide variants in the human genome , 2014, Nucleic acids research.

[46]  G. Comi,et al.  SOD1 misplacing and mitochondrial dysfunction in amyotrophic lateral sclerosis pathogenesis , 2015, Front. Cell. Neurosci..

[47]  F. Coppedè,et al.  DNA damage in neurodegenerative diseases. , 2015, Mutation research.

[48]  Brittany N. Lasseigne,et al.  Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways , 2015, Science.

[49]  Jane S. Paulsen,et al.  Identification of Genetic Factors that Modify Clinical Onset of Huntington’s Disease , 2015, Cell.

[50]  T. Wieland,et al.  NEK1 mutations in familial amyotrophic lateral sclerosis. , 2016, Brain : a journal of neurology.

[51]  E. Boerwinkle,et al.  dbNSFP v3.0: A One‐Stop Database of Functional Predictions and Annotations for Human Nonsynonymous and Splice‐Site SNVs , 2016, Human mutation.