Carriership of two copies of C9orf72 hexanucleotide repeat intermediate-length alleles is a risk factor for ALS in the F
- PDF / 931,178 Bytes
- 9 Pages / 595.276 x 790.866 pts Page_size
- 57 Downloads / 167 Views
Open Access
RESEARCH
Carriership of two copies of C9orf72 hexanucleotide repeat intermediate‑length alleles is a risk factor for ALS in the Finnish population Karri Kaivola1,2* , Samuli J. Salmi1,2, Lilja Jansson1,2, Jyrki Launes3 , Laura Hokkanen3 , Anna‑Kaisa Niemi4,5,6, Kari Majamaa4,5, Jari Lahti3 , Johan G. Eriksson7,8,9, Timo Strandberg10,11, Hannu Laaksovirta1,2† and Pentti J. Tienari1,2†
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 intermediatelength 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 confirma‑ tory 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. Keywords: ALS, C9orf72, Intermediate repeats, Case-control analysis, Aging Introduction The C9orf72 hexanucleotide repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in *Correspondence: [email protected] † Hannu Laaksovirta and Pentti J. Tienari have contributed equally to this work 1 Translational Immunology, Research Programs Unit, University of Helsinki, Helsinki, Finland Full list of author information is available at the end of the article
populations of European descent [7, 16, 21]. Pathological expansions are usually hundreds to thousands of repeats in length [2, 25] and the expansion can exhibit somatic mosaicism [2]. The minimum pathogenic repeat length is unknown, but the threshold of 30 repeats has been commonly used. This threshold might be underestimated since we recently found that about 0.4% of aged Finns carried 30–45 repeat alleles and these individuals had no apparent increase in the frequency of neurode
Data Loading...
