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

Acta Neuropathologica Communications

Timo Strandberg¹  Johan G. Eriksson²  Laura Hokkanen³  Jari Lahti³  Jyrki Launes³  Kari Majamaa⁴  Anna-Kaisa Niemi⁵  Hannu Laaksovirta⁶  Lilja Jansson⁶  Karri Kaivola⁶  Pentti J. Tienari⁶  Samuli J. Salmi⁶ 

[1] Center for Life Course Health Research/Geriatrics, University of Oulu, Oulu, Finland;Department of Medicine, Geriatric Clinic, University of Helsinki, Helsinki University Central Hospital, Helsinki, Finland;Department 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;Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland;Folkhälsan Research Center, Helsinki, Finland;Department of Psychology and Logopedics, University of Helsinki, P.O. Box 21, 00014, Helsinki, Finland;Research Unit of Clinical Neuroscience, Neurology, University of Oulu, P.O. Box 5000, 90014, Oulu, Finland;Department of Neurology and Medical Research Center, Oulu University Hospital, Oulu, Finland;Research Unit of Clinical Neuroscience, Neurology, University of Oulu, P.O. Box 5000, 90014, Oulu, Finland;Department of Neurology and Medical Research Center, Oulu University Hospital, Oulu, Finland;Division of Neonatology, Rady Children’s Hospital San Diego, University of California San Diego, San Diego, CA, USA;Translational Immunology, Research Programs Unit, University of Helsinki, Helsinki, Finland;Department of Neurology, Helsinki University Hospital, P.O. Box 63, 00014, Helsinki, Finland;

关键词: ALS;    C9orf72;    Intermediate repeats;    Case-control analysis;    Aging;   

DOI  :  10.1186/s40478-020-01059-5

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY