University of Oulu

Kaivola, K., Salmi, S.J., Jansson, L. et al. Carriership of two copies of C9orf72 hexanucleotide repeat intermediate-length alleles is a risk factor for ALS in the Finnish population. acta neuropathol commun 8, 187 (2020).

Carriership of two copies of C9orf72 hexanucleotide repeat intermediate-length alleles is a risk factor for ALS in the Finnish population

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Author: Kaivola, Karri1,2; Salmi, Samuli J.1,2; Jansson, Lilja1,2;
Organizations: 1Translational Immunology, Research Programs Unit, University of Helsinki, Helsinki, Finland
2Department of Neurology, Helsinki University Hospital, P.O. Box 63, 00014, Helsinki, Finland
3Department of Psychology and Logopedics, University of Helsinki, P.O. Box 21, 00014, Helsinki, Finland
4Research Unit of Clinical Neuroscience, Neurology, University of Oulu, P.O. Box 5000, 90014, Oulu, Finland
5Department of Neurology and Medical Research Center, Oulu University Hospital, Oulu, Finland
6Division of Neonatology, Rady Children’s Hospital San Diego, University of California San Diego, San Diego, CA, USA
7Department of Obstetrics & Gynaecology and Human Potential Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore and Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
8Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
9Folkhälsan Research Center, Helsinki, Finland
10Center for Life Course Health Research/Geriatrics, University of Oulu, Oulu, Finland
11Department of Medicine, Geriatric Clinic, University of Helsinki, Helsinki University Central Hospital, Helsinki, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.9 MB)
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Language: English
Published: Springer Nature, 2020
Publish Date: 2021-02-12


The hexanucleotide repeat expansion in intron 1 of the C9orf72 gene causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In addition to the effects of the pathogenic expansion, a role of intermediate-length alleles has been suggested in ALS, corticobasal degeneration and Parkinson’s disease. Due to the rarity of intermediate-length alleles with over 20 repeats and the geographical variability in their frequency, large studies that account for population stratification are needed to elucidate their effects. To this aim, we used repeat-primed PCR and confirmatory PCR assays to determine the C9orf72 repeat allele lengths in 705 ALS patients and 3958 controls from Finland. After exclusion of expansion carriers (25.5% of the ALS patients and 0.2% of the controls), we compared the frequency of intermediate-length allele carriers of 525 ALS cases and 3950 controls using several intermediate-length allele thresholds (7–45, 17–45, 21–45, 24–45 and 24–30). The carriership of an intermediate-length allele did not associate with ALS (Fisher’s test, all p ≥ 0.15) nor was there any association with survival (p ≥ 0.33), when we divided our control group into three age groups (18–65, 66–84 and 85–105 years). Carriership of two intermediate-length alleles was associated with ALS, when the longer allele was ≥ 17 repeats (p = 0.002, OR 5.32 95% CI 2.02–14.05) or ≥ 21 repeats (p = 0.00016, OR 15.21 95% CI 3.79–61.0). Our results show that intermediate-length alleles are a risk factor of ALS when present in both alleles, whereas carrying just one intermediate-length allele was not associated with ALS or survival.

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Series: Acta neuropathologica communications
ISSN: 2051-5960
ISSN-E: 2051-5960
ISSN-L: 2051-5960
Volume: 8
Issue: 1
Article number: 187
DOI: 10.1186/s40478-020-01059-5
Type of Publication: A1 Journal article – refereed
Field of Science: 1184 Genetics, developmental biology, physiology
Funding: This study was funded by the Finnish Cultural Foundation, the Paulo Foundation and The Finnish Brain Foundation sr, the Sigrid Juselius Foundation, Helsinki University Hospital grants (TYH2018213, TYH2019254), ALS tuttu ry and the Finnish Academy (318868).
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