Iacoangeli, A;
Al Khleifat, A;
Jones, AR;
Sproviero, W;
Shatunov, A;
Opie-Martin, S;
Morrison, KE;
... Al-Chalabi, A; + view all
(2019)
C9orf72 intermediate expansions of 24-30 repeats are associated with ALS.
Acta Neuropathologica Communications
, 7
, Article 115. 10.1186/s40478-019-0724-4.
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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.
| Type: | Article |
|---|---|
| Title: | C9orf72 intermediate expansions of 24-30 repeats are associated with ALS |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1186/s40478-019-0724-4 |
| Publisher version: | https://doi.org/10.1186/s40478-019-0724-4 |
| Language: | English |
| Additional information: | This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/ 1.0/) applies to the data made available in this article, unless otherwise stated. |
| Keywords: | C9orf72, Repeat expansion, ALS, Genetics, Whole-genome sequencing, Next-generation sequencing |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Health Informatics UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Health Informatics > Clinical Epidemiology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10080791 |
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