Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis
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Published:2022-01-28
Issue:1
Volume:7
Page:
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ISSN:2056-7944
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Container-title:npj Genomic Medicine
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language:en
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Short-container-title:npj Genom. Med.
Author:
Al Khleifat AhmadORCID, Iacoangeli Alfredo, van Vugt Joke J. F. A., Bowles Harry, Moisse MatthieuORCID, Zwamborn Ramona A. J., van der Spek Rick A. A.ORCID, Shatunov Aleksey, Cooper-Knock Johnathan, Topp Simon, Byrne RossORCID, Gellera Cinzia, López VictoriaORCID, Jones Ashley R.ORCID, Opie-Martin Sarah, Vural Atay, Campos Yolanda, van Rheenen WouterORCID, Kenna BrendanORCID, Van Eijk Kristel R., Kenna Kevin, Weber Markus, Smith Bradley, Fogh Isabella, Silani Vincenzo, Morrison Karen E.ORCID, Dobson RichardORCID, van Es Michael A.ORCID, McLaughlin Russell L.ORCID, Vourc’h Patrick, Chio AdrianoORCID, Corcia Philippe, de Carvalho MamedeORCID, Gotkine MarcORCID, Panades Monica P., Mora Jesus S.ORCID, Shaw Pamela J., Landers John E.ORCID, Glass Jonathan D.ORCID, Shaw Christopher E., Basak Nazli, Hardiman Orla, Robberecht Wim, Van Damme PhilipORCID, van den Berg Leonard H., Veldink Jan H.ORCID, Al-Chalabi AmmarORCID
Abstract
AbstractThere is a strong genetic contribution to Amyotrophic lateral sclerosis (ALS) risk, with heritability estimates of up to 60%. Both Mendelian and small effect variants have been identified, but in common with other conditions, such variants only explain a little of the heritability. Genomic structural variation might account for some of this otherwise unexplained heritability. We therefore investigated association between structural variation in a set of 25 ALS genes, and ALS risk and phenotype. As expected, the repeat expansion in the C9orf72 gene was identified as associated with ALS. Two other ALS-associated structural variants were identified: inversion in the VCP gene and insertion in the ERBB4 gene. All three variants were associated both with increased risk of ALS and specific phenotypic patterns of disease expression. More than 70% of people with respiratory onset ALS harboured ERBB4 insertion compared with 25% of the general population, suggesting respiratory onset ALS may be a distinct genetic subtype.
Funder
Motor Neurone Disease Association RCUK | MRC | Medical Research Foundation Wellcome Trust
Publisher
Springer Science and Business Media LLC
Subject
Genetics (clinical),Genetics,Molecular Biology
Reference56 articles.
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