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

Ahmad Al Khleifat; Alfredo Iacoangeli; Joke J F A van Vugt; Harry Bowles; Matthieu Moisse; Ramona A J Zwamborn; Rick A A van der Spek; Aleksey Shatunov; Johnathan Cooper-Knock; Simon Topp; Ross Byrne; Cinzia Gellera; Victoria López; Ashley R Jones; Sarah Opie-Martin; Atay Vural; Yolanda Campos; Wouter van Rheenen; Brendan Kenna; Kristel R Van Eijk; Kevin Kenna; Markus Weber; Bradley Smith; Isabella Fogh; Vincenzo Silani; Karen E Morrison; Richard Dobson; Michael A van Es; Russell L McLaughlin; Patrick Vourc'h; Adriano Chio; Philippe Corcia; Mamede de Carvalho; Marc Gotkine; Monica P Panades; Jesus S Mora; Pamela J Shaw; John E Landers; Jonathan D Glass; Christopher E Shaw; Nazli Basak; Orla Hardiman; Wim Robberecht; Philip Van Damme; Leonard H van den Berg; Jan H Veldink; Ammar Al-Chalabi

doi:10.1038/s41525-021-00267-9

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

Ahmad Al Khleifat, Alfredo Iacoangeli, Joke J F A van Vugt, Harry Bowles, Matthieu Moisse, Ramona A J Zwamborn, Rick A A van der Spek, Aleksey Shatunov, Johnathan Cooper-Knock, Simon Topp, Ross Byrne, Cinzia Gellera, Victoria López, Ashley R Jones, Sarah Opie-Martin, Atay Vural, Yolanda Campos, Wouter van Rheenen, Brendan Kenna, Kristel R Van EijkKevin Kenna, Markus Weber, Bradley Smith, Isabella Fogh, Vincenzo Silani, Karen E Morrison, Richard Dobson, Michael A van Es, Russell L McLaughlin, Patrick Vourc'h, Adriano Chio, Philippe Corcia, Mamede de Carvalho, Marc Gotkine, Monica P Panades, Jesus S Mora, Pamela J Shaw, John E Landers, Jonathan D Glass, Christopher E Shaw, Nazli Basak, Orla Hardiman, Wim Robberecht, Philip Van Damme, Leonard H van den Berg, Jan H Veldink, Ammar Al-Chalabi

School of Medicine, Dentistry and Biomedical Sciences

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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.

Original language	English
Article number	8
Journal	NPJ Genomic Medicine
Volume	7
Issue number	1
DOIs	https://doi.org/10.1038/s41525-021-00267-9
Publication status	Published - 28 Jan 2022

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Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis
Copyright 2022 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
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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., Topp, S., Byrne, R., Gellera, C., López, V., Jones, A. R., Opie-Martin, S., Vural, A., Campos, Y., van Rheenen, W., Kenna, B., ... Al-Chalabi, A. (2022). Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis. NPJ Genomic Medicine, 7(1), [8]. https://doi.org/10.1038/s41525-021-00267-9

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title = "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.",

author = "{Al Khleifat}, Ahmad and Alfredo Iacoangeli and {van Vugt}, {Joke J F A} and Harry Bowles and Matthieu Moisse and Zwamborn, {Ramona A J} and {van der Spek}, {Rick A A} and Aleksey Shatunov and Johnathan Cooper-Knock and Simon Topp and Ross Byrne and Cinzia Gellera and Victoria L{\'o}pez and Jones, {Ashley R} and Sarah Opie-Martin and Atay Vural and Yolanda Campos and {van Rheenen}, Wouter and Brendan Kenna and {Van Eijk}, {Kristel R} and Kevin Kenna and Markus Weber and Bradley Smith and Isabella Fogh and Vincenzo Silani and Morrison, {Karen E} and Richard Dobson and {van Es}, {Michael A} and McLaughlin, {Russell L} and Patrick Vourc'h and Adriano Chio and Philippe Corcia and {de Carvalho}, Mamede and Marc Gotkine and Panades, {Monica P} and Mora, {Jesus S} and Shaw, {Pamela J} and Landers, {John E} and Glass, {Jonathan D} and Shaw, {Christopher E} and Nazli Basak and Orla Hardiman and Wim Robberecht and {Van Damme}, Philip and {van den Berg}, {Leonard H} and Veldink, {Jan H} and Ammar Al-Chalabi",

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Al Khleifat, A, Iacoangeli, A, van Vugt, JJFA, Bowles, H, Moisse, M, Zwamborn, RAJ, van der Spek, RAA, Shatunov, A, Cooper-Knock, J, Topp, S, Byrne, R, Gellera, C, López, V, Jones, AR, Opie-Martin, S, Vural, A, Campos, Y, van Rheenen, W, Kenna, B, Van Eijk, KR, Kenna, K, Weber, M, Smith, B, Fogh, I, Silani, V, Morrison, KE, Dobson, R, van Es, MA, McLaughlin, RL, Vourc'h, P, Chio, A, Corcia, P, de Carvalho, M, Gotkine, M, Panades, MP, Mora, JS, Shaw, PJ, Landers, JE, Glass, JD, Shaw, CE, Basak, N, Hardiman, O, Robberecht, W, Van Damme, P, van den Berg, LH, Veldink, JH & Al-Chalabi, A 2022, 'Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis', NPJ Genomic Medicine, vol. 7, no. 1, 8. https://doi.org/10.1038/s41525-021-00267-9

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T1 - Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis

AU - Al Khleifat, Ahmad

AU - Iacoangeli, Alfredo

AU - van Vugt, Joke J F A

AU - Bowles, Harry

AU - Moisse, Matthieu

AU - Zwamborn, Ramona A J

AU - van der Spek, Rick A A

AU - Shatunov, Aleksey

AU - Cooper-Knock, Johnathan

AU - Topp, Simon

AU - Byrne, Ross

AU - Gellera, Cinzia

AU - López, Victoria

AU - Jones, Ashley R

AU - Opie-Martin, Sarah

AU - Vural, Atay

AU - Campos, Yolanda

AU - van Rheenen, Wouter

AU - Kenna, Brendan

AU - Van Eijk, Kristel R

AU - Kenna, Kevin

AU - Weber, Markus

AU - Smith, Bradley

AU - Fogh, Isabella

AU - Silani, Vincenzo

AU - Morrison, Karen E

AU - Dobson, Richard

AU - van Es, Michael A

AU - McLaughlin, Russell L

AU - Vourc'h, Patrick

AU - Chio, Adriano

AU - Corcia, Philippe

AU - de Carvalho, Mamede

AU - Gotkine, Marc

AU - Panades, Monica P

AU - Mora, Jesus S

AU - Shaw, Pamela J

AU - Landers, John E

AU - Glass, Jonathan D

AU - Shaw, Christopher E

AU - Basak, Nazli

AU - Hardiman, Orla

AU - Robberecht, Wim

AU - Van Damme, Philip

AU - van den Berg, Leonard H

AU - Veldink, Jan H

AU - Al-Chalabi, Ammar

PY - 2022/1/28

Y1 - 2022/1/28

N2 - 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.

AB - 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.

U2 - 10.1038/s41525-021-00267-9

DO - 10.1038/s41525-021-00267-9

M3 - Article

VL - 7

JO - NPJ Genomic Medicine

JF - NPJ Genomic Medicine

SN - 2056-7944

IS - 1

M1 - 8

ER -

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

Abstract

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