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A large genome scan for rare CNVs in amyotrophic lateral sclerosis
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
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2010 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 19, no 20, 4091-4099 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Oxford Journals , 2010. Vol. 19, no 20, 4091-4099 p.
URN: urn:nbn:se:umu:diva-42185DOI: 10.1093/hmg/ddq323ISI: 000282439700017PubMedID: 20685689OAI: diva2:408863
Available from: 2011-04-06 Created: 2011-04-06 Last updated: 2011-08-18Bibliographically approved

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Andersen, Peter MBirve, Anna
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