Abstract
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.
Highlights
Parkinson’s disease (PD) is a common neurodegenerative disorder, affecting about 2% of the elderly population worldwide [1]
Allele frequencies of chromosome 9 open reading frame 72 (C9orf72) repeats were determined in our cohort of 1106 Ashkenazi PD patients (Table 1), that was divided into two groups based on their genotypic status, either carriers of PD-associated mutations, or non-carrier patients (PD-NC)
We ran a stratified analysis based on the carrier status in leucine-rich repeat kinase 2 (LRRK2), glucosidase β acid (GBA), and sphingomyelin phosphodiesterase 1 (SMPD1), as a high percentage of our PD cohort carry risk alleles in these 3 genes (35.1%, 388/1106), and these carrier-patients may mask the effect of the hexanucleotide repeat length on PD-risk in non-carrier patients
Summary
Parkinson’s disease (PD) is a common neurodegenerative disorder, affecting about 2% of the elderly population worldwide [1]. A wide variety of genetic changes and mechanisms are involved in PD, including rare and common variants, recessive, dominant, and oligogenic inheritance, and epigenetics [2,3,4,5,6,7,8]. Parkinsonism was observed in more than 40% of FTD and FTD/ALS patients with pathogenic C9orf expansions [15]. This observation has led researchers to investigate the possible association of C9orf expansions with PD
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