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Rare genetic variation in UNC13A may modify survival in amyotrophic lateral sclerosis

Rare genetic variation in UNC13A may modify survival in amyotrophic lateral sclerosis
Rare genetic variation in UNC13A may modify survival in amyotrophic lateral sclerosis
Our objective was to identify whether rare genetic variation in amyotrophic lateral sclerosis (ALS) candidate survival genes modifies ALS survival. Candidate genes were selected based on evidence for modifying ALS survival. Each tail of the extreme 1.5% of survival was selected from the UK MND DNA Bank and all samples available underwent whole genome sequencing. A replication set from the Netherlands was used for validation. Sequences of candidate survival genes were extracted and variants passing quality control with a minor allele frequency ?0.05 were selected for association testing. Analysis was by burden testing using SKAT.

Candidate survival genes UNC13A, KIFAP3, and EPHA4 were tested for association in a UK sample comprising 25 short survivors and 25 long survivors. Results showed that only SNVs in UNC13A were associated with survival (p = 6.57?×?10?3). SNV rs10419420:G?>?A was found exclusively in long survivors (3/25) and rs4808092:G?>?A exclusively in short survivors (4/25). These findings were not replicated in a Dutch sample. In conclusion, population specific rare variants of UNC13A may modulate survival in ALS.
2167-8421
1-7
Gaastra, Benjamin
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Shatunov, Aleksey
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Pulit, Sara
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Jones, Ashley R.
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Sproviero, William
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Gillett, Alexandra
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Chen, Zhongbo
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Kirby, Janine
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Fogh, Isabella
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Powell, John F.
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Leigh, P. Nigel
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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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van den Berg, Leonard H.
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Veldink, Jan H.
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Lewis, Cathryn M.
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Al-Chalabi, Ammar
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Gaastra, Benjamin
f48eac25-66e4-4e0b-8325-d4e4b9558d8f
Shatunov, Aleksey
e4422e0f-4878-404a-8e9e-fc45b4d5d9bd
Pulit, Sara
d99ff768-8454-4ac3-8503-2ad6a6aeec21
Jones, Ashley R.
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Sproviero, William
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Gillett, Alexandra
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Chen, Zhongbo
15627e6b-90a4-4c92-8c2a-c18772bf9f5c
Kirby, Janine
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Fogh, Isabella
e24e94f5-e77c-426c-8915-03e02cf56ef1
Powell, John F.
3bd035d2-40a4-457c-a64d-0674173cfb7b
Leigh, P. Nigel
7f764ac0-9010-4831-9236-a40354cf61f9
Morrison, Karen E.
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Shaw, Pamela J.
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Shaw, Christopher E.
ad432fe6-4928-445b-a3e1-aaba83c6a530
van den Berg, Leonard H.
bd6ed390-a56e-48d3-8273-a139bdaca4da
Veldink, Jan H.
7c073868-8350-4d7a-b345-86541b34e3a2
Lewis, Cathryn M.
6608c959-472e-41fe-8d37-dcd9e9240eef
Al-Chalabi, Ammar
db16bbda-7684-49b4-9b2d-9799c7dba33c

Gaastra, Benjamin, Shatunov, Aleksey, Pulit, Sara, Jones, Ashley R., Sproviero, William, Gillett, Alexandra, Chen, Zhongbo, Kirby, Janine, Fogh, Isabella, Powell, John F., Leigh, P. Nigel, Morrison, Karen E., Shaw, Pamela J., Shaw, Christopher E., van den Berg, Leonard H., Veldink, Jan H., Lewis, Cathryn M. and Al-Chalabi, Ammar (2016) Rare genetic variation in UNC13A may modify survival in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 1-7. (doi:10.1080/21678421.2016.1213852).

Record type: Article

Abstract

Our objective was to identify whether rare genetic variation in amyotrophic lateral sclerosis (ALS) candidate survival genes modifies ALS survival. Candidate genes were selected based on evidence for modifying ALS survival. Each tail of the extreme 1.5% of survival was selected from the UK MND DNA Bank and all samples available underwent whole genome sequencing. A replication set from the Netherlands was used for validation. Sequences of candidate survival genes were extracted and variants passing quality control with a minor allele frequency ?0.05 were selected for association testing. Analysis was by burden testing using SKAT.

Candidate survival genes UNC13A, KIFAP3, and EPHA4 were tested for association in a UK sample comprising 25 short survivors and 25 long survivors. Results showed that only SNVs in UNC13A were associated with survival (p = 6.57?×?10?3). SNV rs10419420:G?>?A was found exclusively in long survivors (3/25) and rs4808092:G?>?A exclusively in short survivors (4/25). These findings were not replicated in a Dutch sample. In conclusion, population specific rare variants of UNC13A may modulate survival in ALS.

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Accepted/In Press date: 13 June 2016
e-pub ahead of print date: 1 September 2016
Organisations: Faculty of Medicine

Identifiers

Local EPrints ID: 402879
URI: http://eprints.soton.ac.uk/id/eprint/402879
ISSN: 2167-8421
PURE UUID: 85d239b5-a733-4839-8b78-c5cfed7b3a13
ORCID for Karen E. Morrison: ORCID iD orcid.org/0000-0003-0216-5717

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Date deposited: 15 Nov 2016 09:17
Last modified: 07 Oct 2020 02:09

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Contributors

Author: Benjamin Gaastra
Author: Aleksey Shatunov
Author: Sara Pulit
Author: Ashley R. Jones
Author: William Sproviero
Author: Alexandra Gillett
Author: Zhongbo Chen
Author: Janine Kirby
Author: Isabella Fogh
Author: John F. Powell
Author: P. Nigel Leigh
Author: Karen E. Morrison ORCID iD
Author: Pamela J. Shaw
Author: Christopher E. Shaw
Author: Leonard H. van den Berg
Author: Jan H. Veldink
Author: Cathryn M. Lewis
Author: Ammar Al-Chalabi

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