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A comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the UK

A comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the UK
A comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the UK

Amyotrophic lateral sclerosis is a progressive neurodegenerative disease of motor neurons. About 25 genes have been verified as relevant to the disease process, with rare and common variation implicated. We used next generation sequencing and repeat sizing to comprehensively assay genetic variation in a panel of known amyotrophic lateral sclerosis genes in 1126 patient samples and 613 controls. About 10% of patients were predicted to carry a pathological expansion of the C9orf72 gene. We found an increased burden of rare variants in patients within the untranslated regions of known disease-causing genes, driven by SOD1, TARDBP, FUS, VCP, OPTN and UBQLN2. We found 11 patients (1%) carried more than one pathogenic variant (P = 0.001) consistent with an oligogenic basis of amyotrophic lateral sclerosis. These findings show that the genetic architecture of amyotrophic lateral sclerosis is complex and that variation in the regulatory regions of associated genes may be important in disease pathogenesis.

Amyotrophic lateral sclerosis, Association study, Complex trait, Neurodegeneration, Polygenic inheritance
0006-8950
1611-1618
Morgan, Sarah
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Shatunov, Aleksey
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Sproviero, William
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Jones, Ashley R.
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Shoai, Maryam
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Hughes, Deborah
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Al Khleifat, Ahmad
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Malaspina, Andrea
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Morrison, Karen E.
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Shaw, Pamela J.
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Shaw, Christopher E.
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Sidle, Katie
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Orrell, Richard W.
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Fratta, Pietro
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Hardy, John
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Pittman, Alan
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Al-Chalabi, Ammar
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Morgan, Sarah
2843f219-71cb-4748-bd79-6fa035330eac
Shatunov, Aleksey
e4422e0f-4878-404a-8e9e-fc45b4d5d9bd
Sproviero, William
f0231df6-ec34-456b-976d-d66ec3f3228f
Jones, Ashley R.
4014edfb-94f8-4c42-aaf7-0a437e0182bf
Shoai, Maryam
a34a3c5c-84db-4740-a1b3-cd988c73fa87
Hughes, Deborah
fe320510-1e1c-48cb-811e-2abf271cdeed
Al Khleifat, Ahmad
36f3f499-11a5-4b0a-a617-23d44eab04e9
Malaspina, Andrea
ee322234-33f5-412d-92b5-7ef653a3c69e
Morrison, Karen E.
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Shaw, Pamela J.
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Shaw, Christopher E.
ad432fe6-4928-445b-a3e1-aaba83c6a530
Sidle, Katie
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Orrell, Richard W.
ef3e7a42-0965-4f2f-9ab0-1a645b00b61f
Fratta, Pietro
abcf4158-a4dc-4cec-96b6-2290f7f4b9f1
Hardy, John
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Pittman, Alan
542e5159-e078-46f7-b126-cce2b8d3b47a
Al-Chalabi, Ammar
8ac40bc3-a3c0-47ad-afa7-37e08f7aab6f

Morgan, Sarah, Shatunov, Aleksey, Sproviero, William, Jones, Ashley R., Shoai, Maryam, Hughes, Deborah, Al Khleifat, Ahmad, Malaspina, Andrea, Morrison, Karen E., Shaw, Pamela J., Shaw, Christopher E., Sidle, Katie, Orrell, Richard W., Fratta, Pietro, Hardy, John, Pittman, Alan and Al-Chalabi, Ammar (2017) A comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the UK. Brain, 140 (6), 1611-1618. (doi:10.1093/brain/awx082).

Record type: Article

Abstract

Amyotrophic lateral sclerosis is a progressive neurodegenerative disease of motor neurons. About 25 genes have been verified as relevant to the disease process, with rare and common variation implicated. We used next generation sequencing and repeat sizing to comprehensively assay genetic variation in a panel of known amyotrophic lateral sclerosis genes in 1126 patient samples and 613 controls. About 10% of patients were predicted to carry a pathological expansion of the C9orf72 gene. We found an increased burden of rare variants in patients within the untranslated regions of known disease-causing genes, driven by SOD1, TARDBP, FUS, VCP, OPTN and UBQLN2. We found 11 patients (1%) carried more than one pathogenic variant (P = 0.001) consistent with an oligogenic basis of amyotrophic lateral sclerosis. These findings show that the genetic architecture of amyotrophic lateral sclerosis is complex and that variation in the regulatory regions of associated genes may be important in disease pathogenesis.

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Accepted/In Press date: 5 February 2017
e-pub ahead of print date: 18 April 2017
Published date: 1 June 2017
Keywords: Amyotrophic lateral sclerosis, Association study, Complex trait, Neurodegeneration, Polygenic inheritance

Identifiers

Local EPrints ID: 417053
URI: http://eprints.soton.ac.uk/id/eprint/417053
ISSN: 0006-8950
PURE UUID: 386d67e5-47bb-4d0b-9a51-8e796155eb95
ORCID for Karen E. Morrison: ORCID iD orcid.org/0000-0003-0216-5717

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Date deposited: 18 Jan 2018 17:30
Last modified: 07 Oct 2020 02:09

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Contributors

Author: Sarah Morgan
Author: Aleksey Shatunov
Author: William Sproviero
Author: Ashley R. Jones
Author: Maryam Shoai
Author: Deborah Hughes
Author: Ahmad Al Khleifat
Author: Andrea Malaspina
Author: Karen E. Morrison ORCID iD
Author: Pamela J. Shaw
Author: Christopher E. Shaw
Author: Katie Sidle
Author: Richard W. Orrell
Author: Pietro Fratta
Author: John Hardy
Author: Alan Pittman
Author: Ammar Al-Chalabi

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