Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis

Abstract

There 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.

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Item Type:	Article
Authors/Creators:	Al Khleifat, A. Iacoangeli, A. van Vugt, J.J.F.A. Bowles, H. Moisse, M. Zwamborn, R.A.J. van der Spek, R.A.A. Shatunov, A. Cooper-Knock, J. https://orcid.org/0000-0002-0873-8689 Topp, S. Byrne, R. Gellera, C. López, V. Jones, A.R. Opie-Martin, S. Vural, A. Campos, Y. van Rheenen, W. Kenna, B. Van Eijk, K.R. Kenna, K. Weber, M. Smith, B. Fogh, I. Silani, V. Morrison, K.E. Dobson, R. van Es, M.A. McLaughlin, R.L. Vourc’h, P. Chio, A. Corcia, P. de Carvalho, M. Gotkine, M. Panades, M.P. Mora, J.S. Shaw, P.J. https://orcid.org/0000-0002-8925-2567 Landers, J.E. Glass, J.D. Shaw, C.E. Basak, N. Hardiman, O. Robberecht, W. Van Damme, P. van den Berg, L.H. Veldink, J.H. Al-Chalabi, A.
Copyright, Publisher and Additional Information:	© 2022 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Dates:	Published: 28 January 2022 Published (online): 28 January 2022 Accepted: 21 October 2021
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Sheffield Teaching Hospitals The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield)
Funding Information:	Funder Grant number The Wellcome Trust 216596/Z/19/Z
Depositing User:	Symplectic Sheffield
Date Deposited:	07 Feb 2022 09:12
Last Modified:	07 Feb 2022 09:12
Status:	Published
Publisher:	Springer Nature
Refereed:	Yes
Identification Number:	10.1038/s41525-021-00267-9
Related URLs:	PubMed URL
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:183286

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Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis

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