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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Kaivola, K, Salmi, S J, Jansson, L, Launes, J, Hokkanen, L, Niemi, A-K, Majamaa, K, Lahti, J, Eriksson, J G, Strandberg, T, Laaksovirta, H & Tienari, P J 2020, ' Carriership of two copies of C9orf72 hexanucleotide repeat intermediate-length alleles is a risk factor for ALS in the Finnish population ', Acta Neuropathologica Communications, vol. 8, no. 1, 187 . https://doi.org/10.1186/s40478-020-01059-5

Title: Carriership of two copies of C9orf72 hexanucleotide repeat intermediate-length alleles is a risk factor for ALS in the Finnish population
Author: Kaivola, Karri; Salmi, Samuli J.; Jansson, Lilja; Launes, Jyrki; Hokkanen, Laura; Niemi, Anna-Kaisa; Majamaa, Kari; Lahti, Jari; Eriksson, Johan G.; Strandberg, Timo; Laaksovirta, Hannu; Tienari, Pentti J.
Contributor organization: TRIMM - Translational Immunology Research Program
University of Helsinki
Neurologian yksikkö
Helsinki University Hospital Area
HUS Neurocenter
Clinicum
Research Programs Unit
Medicum
Department of Psychology and Logopedics
Johan Eriksson / Principal Investigator
Department of General Practice and Primary Health Care
HUS Internal Medicine and Rehabilitation
Timo Strandberg / Principal Investigator
Department of Medicine
Geriatrian yksikkö
Department of Neurosciences
Date: 2020-11-09
Language: eng
Number of pages: 9
Belongs to series: Acta Neuropathologica Communications
ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-020-01059-5
URI: http://hdl.handle.net/10138/322712
Abstract: 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.
Subject: ALS
C9orf72
Intermediate repeats
Case-control analysis
Aging
EXPANSIONS
DISEASE
SIZE
3112 Neurosciences
3124 Neurology and psychiatry
515 Psychology
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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