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

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Al Khleifat, Ahmad ORCID: 0000-0002-7406-9831, Iacoangeli, Alfredo, van Vugt, Joke JFA, Bowles, Harry, Moisse, Matthieu ORCID: 0000-0001-8880-9311, Zwamborn, Ramona AJ, van der Spek, Rick AA ORCID: 0000-0001-9983-204X, Shatunov, Aleksey ORCID: 0000-0002-2671-8040, Cooper-Knock, Johnathan ORCID: 0000-0002-0873-8689, Topp, Simon et al (show 37 more authors) , Byrne, Ross ORCID: 0000-0002-4082-6072, Gellera, Cinzia, López, Victoria ORCID: 0000-0001-8129-8352, Jones, Ashley R ORCID: 0000-0003-0470-0058, Opie-Martin, Sarah, Vural, Atay ORCID: 0000-0003-3222-874X, Campos, Yolanda, van Rheenen, Wouter ORCID: 0000-0002-5860-1533, Kenna, Brendan ORCID: 0000-0001-7591-2221, Van Eijk, Kristel R, Kenna, Kevin, Weber, Markus, Smith, Bradley, Fogh, Isabella, Silani, Vincenzo, Morrison, Karen E ORCID: 0000-0003-0216-5717, Dobson, Richard ORCID: 0000-0003-4224-9245, van Es, Michael A ORCID: 0000-0002-7709-5883, McLaughlin, Russell L ORCID: 0000-0003-3915-2135, Vourc'h, Patrick ORCID: 0000-0001-7960-8139, Chio, Adriano ORCID: 0000-0001-9579-5341, Corcia, Philippe, de Carvalho, Mamede ORCID: 0000-0001-7556-0158, Gotkine, Marc ORCID: 0000-0003-2541-6232, Panades, Monica P, Mora, Jesus S ORCID: 0000-0001-6633-5354, Shaw, Pamela J, Landers, John E ORCID: 0000-0001-8084-5043, Glass, Jonathan D ORCID: 0000-0002-3295-4971, Shaw, Christopher E, Basak, Nazli, Hardiman, Orla, Robberecht, Wim, Van Damme, Philip ORCID: 0000-0002-4010-2357, van den Berg, Leonard H, Veldink, Jan H ORCID: 0000-0001-5572-9657 and Al-Chalabi, Ammar ORCID: 0000-0002-4924-7712 (2022) Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis. NPJ genomic medicine, 7 (1). 8-.

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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.

Item Type:	Article
Uncontrolled Keywords:	Neurodegenerative, Genetics, ALS, Rare Diseases, Biotechnology, Neurosciences, Clinical Research, Brain Disorders, Human Genome, 2 Aetiology, 2.1 Biological and endogenous factors, Neurological
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	28 Mar 2023 15:14
Last Modified:	27 Apr 2024 18:56
DOI:	10.1038/s41525-021-00267-9
Open Access URL:	https://doi.org/10.1038/s41525-021-00267-9
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3169329