title: Large-scale screening in sporadic amyotrophic lateral sclerosis identifies genetic modifiers in C9orf72 repeat carriers.
abstract: Sporadic amyotrophic lateral sclerosis (ALS) is considered to be a complex disease with multiple genetic risk factors contributing to the pathogenesis. Identification of genetic risk factors that co-occur frequently could provide relevant insight into underlying mechanisms of motor neuron degeneration. To dissect the genetic architecture of sporadic ALS, we undertook a large sequencing study in 755 apparently sporadic ALS cases and 959 controls, analyzing 10 ALS genes: SOD1, C9orf72, TARDBP, FUS, ANG, CHMP2B, ATXN2, NIPA1, SMN1, and UNC13A. We observed sporadic cases with multiple genetic risk variants in 4.1% compared with 1.3% in controls. The overall difference was not in excess of what is to be expected by chance (binomial test, p = 0.59). We did, however, observe a higher frequency than expected of C9orf72 repeat carriers with co-occurring susceptibility variants (ATXN2, NIPA1, and SMN1; p = 0.001), which is mainly because of the co-occurrence of NIPA1 repeats in 15% of C9orf72 repeat carriers (p = 0.006).
authors.affiliation: Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Annelot M
authors.initials: AM
authors.lastname: Dekker
authors.affiliation: Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Meinie
authors.initials: M
authors.lastname: Seelen
authors.affiliation: Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Perry T C
authors.initials: PT
authors.lastname: van Doormaal
authors.affiliation: Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Wouter
authors.initials: W
authors.lastname: van Rheenen
authors.affiliation: Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Reinoud J P
authors.initials: RJ
authors.lastname: Bothof
authors.affiliation: Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Tim
authors.initials: T
authors.lastname: van Riessen
authors.affiliation: Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: William J
authors.initials: WJ
authors.lastname: Brands
authors.affiliation: Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Anneke J
authors.initials: AJ
authors.lastname: van der Kooi
authors.affiliation: Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Marianne
authors.initials: M
authors.lastname: de Visser
authors.affiliation: Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Nicol C
authors.initials: NC
authors.lastname: Voermans
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: R Jeroen
authors.initials: RJ
authors.lastname: Pasterkamp
authors.affiliation: Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Veldink
authors.affiliation: Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Leonard H
authors.initials: LH
authors.lastname: van den Berg
authors.affiliation: Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address: m.a.vanes@umcutrecht.nl.
authors.forename: Michael A
authors.initials: MA
authors.lastname: van Es
mesh_terms: D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000073885:C9orf72 Protein; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D014644:Genetic Variation; D006579:Heterozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D011506:Proteins / Q000235:genetics*; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics*; D012307:Risk Factors
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D008565:Membrane Proteins; C478824:NIPA1 protein, human; D011506:Proteins
keywords: Amyotrophic lateral sclerosis; C9orf72; Genetic modifiers; NIPA1; Repeat expansions