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C9orf72 intermediate expansions of 24-30 repeats are associated with ALS

C9orf72 intermediate expansions of 24-30 repeats are associated with ALS
C9orf72 intermediate expansions of 24-30 repeats are associated with ALS

The expansion of a hexanucleotide repeat GGGGCC in C9orf72 is the most common known cause of ALS accounting for ~ 40% familial cases and ~ 7% sporadic cases in the European population. In most people, the repeat length is 2, but in people with ALS, hundreds to thousands of repeats may be observed. A small proportion of people have an intermediate expansion, of the order of 20 to 30 repeats in size, and it remains unknown whether intermediate expansions confer risk of ALS in the same way that massive expansions do. We investigated the association of this intermediate repeat with ALS by performing a meta-analysis of four previously published studies and a new British/Alzheimer's Disease Neuroimaging Initiative dataset of 1295 cases and 613 controls. The final dataset comprised 5071 cases and 3747 controls. Our meta-analysis showed association between ALS and intermediate C9orf72 repeats of 24 to 30 repeats in size (random-effects model OR = 4.2, 95% CI = 1.23-14.35, p-value = 0.02). Furthermore, we showed a different frequency of the repeat between the northern and southern European populations (Fisher's exact test p-value = 5 × 10- 3). Our findings provide evidence for the association between intermediate repeats and ALS (p-value = 2 × 10- 4) with direct relevance for research and clinical practice by showing that an expansion of 24 or more repeats should be considered pathogenic.

2051-5960
Iacoangeli, Alfredo
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Al Khleifat, Ahmad
36f3f499-11a5-4b0a-a617-23d44eab04e9
Jones, Ashley R.
4014edfb-94f8-4c42-aaf7-0a437e0182bf
Sproviero, William
f0231df6-ec34-456b-976d-d66ec3f3228f
Shatunov, Aleksey
e4422e0f-4878-404a-8e9e-fc45b4d5d9bd
Opie-Martin, Sarah
9030499e-3b21-45f6-bd50-43fdcc3d3059
Morrison, Karen E.
f00890f0-2fde-4dbd-a73b-7422e1b0ede8
Shaw, Pamela J.
3d0a5c6f-9610-45be-a0bc-5b6888003028
Shaw, Christopher E.
ad432fe6-4928-445b-a3e1-aaba83c6a530
Fogh, Isabella
e24e94f5-e77c-426c-8915-03e02cf56ef1
Dobson, Richard J.
e91de51e-884d-4716-bb55-f312b4c6cd0a
Newhouse, Stephen J.
6bd2356a-2350-4a28-90bf-5386978dad46
Al-Chalabi, Ammar
8ac40bc3-a3c0-47ad-afa7-37e08f7aab6f
Alzheimer’s Disease Neuroimaging Initiative
Iacoangeli, Alfredo
50f630e7-cf3a-4040-9294-ab567fce82d7
Al Khleifat, Ahmad
36f3f499-11a5-4b0a-a617-23d44eab04e9
Jones, Ashley R.
4014edfb-94f8-4c42-aaf7-0a437e0182bf
Sproviero, William
f0231df6-ec34-456b-976d-d66ec3f3228f
Shatunov, Aleksey
e4422e0f-4878-404a-8e9e-fc45b4d5d9bd
Opie-Martin, Sarah
9030499e-3b21-45f6-bd50-43fdcc3d3059
Morrison, Karen E.
f00890f0-2fde-4dbd-a73b-7422e1b0ede8
Shaw, Pamela J.
3d0a5c6f-9610-45be-a0bc-5b6888003028
Shaw, Christopher E.
ad432fe6-4928-445b-a3e1-aaba83c6a530
Fogh, Isabella
e24e94f5-e77c-426c-8915-03e02cf56ef1
Dobson, Richard J.
e91de51e-884d-4716-bb55-f312b4c6cd0a
Newhouse, Stephen J.
6bd2356a-2350-4a28-90bf-5386978dad46
Al-Chalabi, Ammar
8ac40bc3-a3c0-47ad-afa7-37e08f7aab6f

Iacoangeli, Alfredo, Al Khleifat, Ahmad, Jones, Ashley R., Sproviero, William, Shatunov, Aleksey, Opie-Martin, Sarah, Morrison, Karen E., Shaw, Pamela J., Shaw, Christopher E., Fogh, Isabella, Dobson, Richard J., Newhouse, Stephen J. and Al-Chalabi, Ammar , Alzheimer’s Disease Neuroimaging Initiative (2019) C9orf72 intermediate expansions of 24-30 repeats are associated with ALS. Acta Neuropathologica Communications, 7 (1), [115]. (doi:10.1186/s40478-019-0724-4).

Record type: Article

Abstract

The expansion of a hexanucleotide repeat GGGGCC in C9orf72 is the most common known cause of ALS accounting for ~ 40% familial cases and ~ 7% sporadic cases in the European population. In most people, the repeat length is 2, but in people with ALS, hundreds to thousands of repeats may be observed. A small proportion of people have an intermediate expansion, of the order of 20 to 30 repeats in size, and it remains unknown whether intermediate expansions confer risk of ALS in the same way that massive expansions do. We investigated the association of this intermediate repeat with ALS by performing a meta-analysis of four previously published studies and a new British/Alzheimer's Disease Neuroimaging Initiative dataset of 1295 cases and 613 controls. The final dataset comprised 5071 cases and 3747 controls. Our meta-analysis showed association between ALS and intermediate C9orf72 repeats of 24 to 30 repeats in size (random-effects model OR = 4.2, 95% CI = 1.23-14.35, p-value = 0.02). Furthermore, we showed a different frequency of the repeat between the northern and southern European populations (Fisher's exact test p-value = 5 × 10- 3). Our findings provide evidence for the association between intermediate repeats and ALS (p-value = 2 × 10- 4) with direct relevance for research and clinical practice by showing that an expansion of 24 or more repeats should be considered pathogenic.

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Accepted/In Press date: 16 April 2019
Published date: 17 July 2019

Identifiers

Local EPrints ID: 432892
URI: http://eprints.soton.ac.uk/id/eprint/432892
ISSN: 2051-5960
PURE UUID: 0f72e3d4-77b4-4771-8954-12ceb064cf0d
ORCID for Karen E. Morrison: ORCID iD orcid.org/0000-0003-0216-5717

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Date deposited: 31 Jul 2019 16:30
Last modified: 16 Mar 2024 02:59

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Contributors

Author: Alfredo Iacoangeli
Author: Ahmad Al Khleifat
Author: Ashley R. Jones
Author: William Sproviero
Author: Aleksey Shatunov
Author: Sarah Opie-Martin
Author: Karen E. Morrison ORCID iD
Author: Pamela J. Shaw
Author: Christopher E. Shaw
Author: Isabella Fogh
Author: Richard J. Dobson
Author: Stephen J. Newhouse
Author: Ammar Al-Chalabi
Corporate Author: Alzheimer’s Disease Neuroimaging Initiative

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