title: A large genome scan for rare CNVs in amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease selectively affecting motor neurons in the brain and spinal cord. Recent genome-wide association studies (GWASs) have identified several common variants which increase disease susceptibility. In contrast, rare copy-number variants (CNVs), which have been associated with several neuropsychiatric traits, have not been studied for ALS in well-powered study populations. To examine the role of rare CNVs in ALS susceptibility, we conducted a CNV association study including over 19,000 individuals. In a genome-wide screen of 1875 cases and 8731 controls, we did not find evidence for a difference in global CNV burden between cases and controls. In our association analyses, we identified two loci that met our criteria for follow-up: the DPP6 locus (OR = 3.59, P = 6.6 × 10(-3)), which has already been implicated in ALS pathogenesis, and the 15q11.2 locus, containing NIPA1 (OR = 12.46, P = 9.3 × 10(-5)), the gene causing hereditary spastic paraparesis type 6 (HSP 6). We tested these loci in a replication cohort of 2559 cases and 5887 controls. Again, results were suggestive of association, but did not meet our criteria for independent replication: DPP6 locus: OR = 1.92, P = 0.097, pooled results: OR = 2.64, P = 1.4 × 10(-3); NIPA1: OR = 3.23, P = 0.041, pooled results: OR = 6.20, P = 2.2 × 10(-5)). Our results highlight DPP6 and NIPA1 as candidates for more in-depth studies. Unlike other complex neurological and psychiatric traits, rare CNVs with high effect size do not play a major role in ALS pathogenesis.
authors.affiliation: Department of Neurology, Rudolf Magnus Institute of Neuroscience, Genetics, University Medical Centre Utrecht, 3584 CX Utrecht, The Netherlands.
authors.forename: Hylke M
authors.initials: HM
authors.lastname: Blauw
authors.forename: Ammar
authors.initials: A
authors.lastname: Al-Chalabi
authors.forename: Peter M
authors.initials: PM
authors.lastname: Andersen
authors.forename: Paul W J
authors.initials: PW
authors.lastname: van Vught
authors.forename: Frank P
authors.initials: FP
authors.lastname: Diekstra
authors.forename: Michael A
authors.initials: MA
authors.lastname: van Es
authors.forename: Christiaan G J
authors.initials: CG
authors.lastname: Saris
authors.forename: Ewout J N
authors.initials: EJ
authors.lastname: Groen
authors.forename: Wouter
authors.initials: W
authors.lastname: van Rheenen
authors.forename: Max
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authors.lastname: Koppers
authors.forename: Ruben
authors.initials: R
authors.lastname: Van't Slot
authors.forename: Eric
authors.initials: E
authors.lastname: Strengman
authors.forename: Karol
authors.initials: K
authors.lastname: Estrada
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Lambertus A
authors.initials: LA
authors.lastname: Kiemeney
authors.forename: Sita H M
authors.initials: SH
authors.lastname: Vermeulen
authors.forename: Anna
authors.initials: A
authors.lastname: Birve
authors.forename: Stefan
authors.initials: S
authors.lastname: Waibel
authors.forename: Thomas
authors.initials: T
authors.lastname: Meyer
authors.forename: Simon
authors.initials: S
authors.lastname: Cronin
authors.forename: Russell L
authors.initials: RL
authors.lastname: McLaughlin
authors.forename: Orla
authors.initials: O
authors.lastname: Hardiman
authors.forename: Peter C
authors.initials: PC
authors.lastname: Sapp
authors.forename: Martin D
authors.initials: MD
authors.lastname: Tobin
authors.forename: Louise V
authors.initials: LV
authors.lastname: Wain
authors.forename: Barbara
authors.initials: B
authors.lastname: Tomik
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Slowik
authors.forename: Robin
authors.initials: R
authors.lastname: Lemmens
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
authors.forename: Claudia
authors.initials: C
authors.lastname: Schulte
authors.forename: Thomas
authors.initials: T
authors.lastname: Gasser
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
authors.forename: John E
authors.initials: JE
authors.lastname: Landers
authors.forename: Wim
authors.initials: W
authors.lastname: Robberecht
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.forename: Roel A
authors.initials: RA
authors.lastname: Ophoff
authors.forename: Jan H
authors.initials: JH
authors.lastname: Veldink
authors.forename: Leonard H
authors.initials: LH
authors.lastname: van den Berg
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D016022:Case-Control Studies; D056915:DNA Copy Number Variations; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D009046:Motor Neurons; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D015221:Potassium Channels / Q000235:genetics*; D012307:Risk Factors; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics
chemical_list: D008565:Membrane Proteins; C478824:NIPA1 protein, human; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; C503535:DPP6 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases