Title: A large genome scan for rare CNVs in amyotrophic lateral sclerosis
Authors: Blauw, Hylke M ×
Al-Chalabi, Ammar
Andersen, Peter M
van Vught, Paul W J
Diekstra, Frank P
van Es, Michael A
Saris, Christiaan G J
Groen, Ewout J N
van Rheenen, Wouter
Koppers, Max
Van't Slot, Ruben
Strengman, Eric
Estrada, Karol
Rivadeneira, Fernando
Hofman, Albert
Uitterlinden, Andre G
Kiemeney, Lambertus A
Vermeulen, Sita H M
Birve, Anna
Waibel, Stefan
Meyer, Thomas
Cronin, Simon
McLaughlin, Russell L
Hardiman, Orla
Sapp, Peter C
Tobin, Martin D
Wain, Louise V
Tomik, Barbara
Slowik, Agnieszka
Lemmens, Robin
Rujescu, Dan
Schulte, Claudia
Gasser, Thomas
Brown, Robert H
Landers, John E
Robberecht, Wim
Ludolph, Albert C
Ophoff, Roel A
Veldink, Jan H
van den Berg, Leonard H #
Issue Date: Oct-2010
Publisher: IRL Press
Series Title: Human Molecular Genetics vol:19 issue:20 pages:4091-9
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.
ISSN: 0964-6906
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory for Neurobiology (Vesalius Research Center)
× corresponding author
# (joint) last author

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