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

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 structura...

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Detalles Bibliográficos
Autores: Al Khleifat, Ahmad, Iacoangeli, Alfredo, Vugt, Joke J. F. A. van, Bowles, Harry, Moisse, Matthieu, Zwamborn, Ramona A. J., Spek, Rick A. A. van der, Shatunov, Aleksey, Cooper-Knock, Johnathan, Topp, Simon, Byrne, Ross, Gellera, Cinzia, López, Victoria, Jones, Ashley R., Opie Martin, Sarah, Vural, Atay, Campos, Yolanda, Rheenen, Wouter van, Kenna, Brendan, Eijk, Kristel R. van, Kenna, Kevin, Weber, Markus, Smith, Bradley, Fogh, Isabella, Silani, Vincenzo, Morrison, Karen E., Dobson, Richard, Es, Michael A. van, Mclaughlin, Russell L., Vourc’h, Patrick, Chio, Adriano, Corcia, Philippe, Carvalho, Mamede de, Gotkine, Marc, Panades, Monica P., Mora, Jesus S., Shaw, Pamela J., Landers, John E., Glass, Jonathan D., Shaw, Christopher E., Basak, Nazli, Hardiman, Orla, Robberecht, Wim, Damme, Philip van, Berg, Leonard H. van der, Veldink, Jan H., Al Chalabi, Ammar
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/183102
Acceso en línea:https://hdl.handle.net/2445/183102
Access Level:acceso abierto
Palabra clave:Esclerosi lateral amiotròfica
Genètica humana
Amyotrophic lateral sclerosis
Human genetics
Descripción
Sumario: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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