학술논문
Carriership of two copies of C9orf72 hexanucleotide repeat intermediate-length alleles is a risk factor for ALS in the Finnish population
Document Type
Academic Journal
Author
Source
Acta Neuropathologica Communications. November 9, 2020, Vol. 8 Issue 1
Subject
Language
English
ISSN
2051-5960
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 [greater than or equai to] 0.15) nor was there any association with survival (p [greater than or equai to] 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 [greater than or equai to] 17 repeats (p = 0.002, OR 5.32 95% CI 2.02-14.05) or [greater than or equai to] 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. Keywords: ALS, C9orf72, Intermediate repeats, Case-control analysis, Aging
Author(s): Karri Kaivola[sup.1,2], Samuli J. Salmi[sup.1,2], Lilja Jansson[sup.1,2], Jyrki Launes[sup.3], Laura Hokkanen[sup.3], Anna-Kaisa Niemi[sup.4,5,6], Kari Majamaa[sup.4,5], Jari Lahti[sup.3], Johan G. Eriksson[sup.7,8,9], Timo Strandberg[sup.10,11], Hannu Laaksovirta[sup.1,2] and Pentti J. Tienari[sup.1,2] Introduction [...]
Author(s): Karri Kaivola[sup.1,2], Samuli J. Salmi[sup.1,2], Lilja Jansson[sup.1,2], Jyrki Launes[sup.3], Laura Hokkanen[sup.3], Anna-Kaisa Niemi[sup.4,5,6], Kari Majamaa[sup.4,5], Jari Lahti[sup.3], Johan G. Eriksson[sup.7,8,9], Timo Strandberg[sup.10,11], Hannu Laaksovirta[sup.1,2] and Pentti J. Tienari[sup.1,2] Introduction [...]