C9orf72-g4c2 intermediate repeats and parkinson’s disease; a data-driven hypothesis

Hila Kobo, Orly Goldstein, Mali Gana-Weisz, Anat Bar-Shira, Tanya Gurevich, Avner Thaler, Anat Mirelman, Nir Giladi, Avi Orr-Urtreger*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Pathogenic C9orf72-G4C2 repeat expansions are associated with ALS/FTD, but not with Parkinson’s disease (PD); yet the possible link between intermediate repeat lengths and PD remains inconclusive. We aim to study the potential involvement of these repeats in PD. The number of C9orf72-repeats were determined by flanking and repeat-primed PCR assays, and the risk-haplotype was determined by SNP-array. Their association with PD was assessed in a stratified manner: in PD-patients-carriers of mutations in LRRK2, GBA, or SMPD1 genes (n = 388), and in PD-non-carriers (NC, n = 718). Allelic distribution was significantly different only in PD-NC compared to 600 controls when looking both at the allele with higher repeat’s size (p = 0.034) and at the combined number of repeats from both alleles (p = 0.023). Intermediate repeats (20–60 repeats) were associated with PD in PD-NC patients (p = 0.041; OR = 3.684 (CI 1.05–13.0)) but not in PD-carriers (p = 0.684). The C9orf72 risk-haplotype, determined in a subgroup of 588 PDs and 126 controls, was observed in higher frequency in PD-NC (dominant model, OR = 1.71, CI 1.04–2.81, p = 0.0356). All 19 alleles within the risk-haplotype were associated with higher C9orf72 RNA levels according to the GTEx database. Based on our data, we suggest a model in which intermediate repeats are a risk factor for PD in non-carriers, driven not only by the number of repeats but also by the variants’ genotypes within the risk-haplotype. Further studies are needed to elucidate this possible role of C9orf72 in PD pathogenesis.

Original languageEnglish
Article number1210
Issue number8
StatePublished - Aug 2021


FundersFunder number
Kahn Foundation
Michael J. Fox Foundation for Parkinson's Research


    • C9orf72
    • Hexanucleotide expansions
    • Intermediate repeats
    • Parkinson’s disease (PD)


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