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 wellpowered 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.

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Keywords amyotrophic lateral sclerosis, article, controlled study, copy number variation, disease predisposition, follow up, gene deletion, gene duplication, gene locus, gene replication, genetic analysis, genetic association, genotype, hereditary motor sensory neuropathy, human, linkage analysis, major clinical study, priority journal, real time polymerase chain reaction
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Journal Human Molecular Genetics
Blauw, H.M, Al-Chalabi, A, Andersen, P.M, van Vught, P.W.J, Diekstra, F.P, van Es, M.A, … van den Berg, L.H. (2010). A large genome scan for rare CNVs in amyotrophic lateral sclerosis. Human Molecular Genetics, 19(20), 4091–4099. doi:10.1093/hmg/ddq323