title: Genetic epidemiology of motor neuron disease-associated variants in the Scottish population.
abstract: Genetic understanding of motor neuron disease (MND) has evolved greatly in the past 10 years, including the recent identification of association between MND and variants in TBK1 and NEK1. Our aim was to determine the frequency of pathogenic variants in known MND genes and to assess whether variants in TBK1 and NEK1 contribute to the burden of MND in the Scottish population. SOD1, TARDBP, OPTN, TBK1, and NEK1 were sequenced in 441 cases and 400 controls. In addition to 44 cases known to carry a C9orf72 hexanucleotide repeat expansion, we identified 31 cases and 2 controls that carried a loss-of-function or pathogenic variant. Loss-of-function variants were found in TBK1 in 3 cases and no controls and, separately, in NEK1 in 3 cases and no controls. This study provides an accurate description of the genetic epidemiology of MND in Scotland and provides support for the contribution of both TBK1 and NEK1 to MND susceptibility in the Scottish population.
authors.affiliation: Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: Holly A
authors.initials: HA
authors.lastname: Black
authors.affiliation: The Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, UK; Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Danielle J
authors.initials: DJ
authors.lastname: Leighton
authors.affiliation: The Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, UK; Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK; South East Scotland Genetics Service, Western General Hospital, Edinburgh, UK.
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Cleary
authors.affiliation: Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: Elaine
authors.initials: E
authors.lastname: Rose
authors.affiliation: The Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, UK; Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Stephenson
authors.affiliation: The Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, UK; Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Shuna
authors.initials: S
authors.lastname: Colville
authors.affiliation: Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: David
authors.initials: D
authors.lastname: Ross
authors.affiliation: South East Scotland Genetics Service, Western General Hospital, Edinburgh, UK.
authors.forename: Jon
authors.initials: J
authors.lastname: Warner
authors.affiliation: South East Scotland Genetics Service, Western General Hospital, Edinburgh, UK.
authors.forename: Mary
authors.initials: M
authors.lastname: Porteous
authors.affiliation: The Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, UK.
authors.forename: George H
authors.initials: GH
authors.lastname: Gorrie
authors.affiliation: The Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Swingler
authors.affiliation: Institute for Genomic Medicine, Columbia University, New York, USA.
authors.forename: David
authors.initials: D
authors.lastname: Goldstein
authors.affiliation: Institute for Genomic Medicine, Columbia University, New York, USA.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Harms
authors.affiliation: Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Connick
authors.affiliation: The Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, UK; Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Suvankar
authors.initials: S
authors.lastname: Pal
authors.affiliation: Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. Electronic address: tim.aitman@ed.ac.uk.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Aitman
authors.affiliation: The Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, UK; Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK. Electronic address: siddharthan.chandran@ed.ac.uk.
authors.forename: Siddharthan
authors.initials: S
authors.lastname: Chandran
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000453:epidemiology* / Q000235:genetics*; D000072380:NIMA-Related Kinase 1 / Q000235:genetics*; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012606:Scotland / Q000453:epidemiology; D055815:Young Adult
chemical_list: C000606914:NEK1 protein, human; D000072380:NIMA-Related Kinase 1; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human
keywords: Amyotrophic lateral sclerosis; Motor neuron disease; NEK1; TBK1