| Summary: | Pathogenic <i>C9orf72</i>-G<sub>4</sub>C<sub>2</sub> 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 <i>C9orf72</i>-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 <i>LRRK2</i>, <i>GBA</i>, or <i>SMPD1</i> genes (<i>n</i> = 388), and in PD-non-carriers (NC, <i>n</i> = 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 (<i>p</i> = 0.034) and at the combined number of repeats from both alleles (<i>p</i> = 0.023). Intermediate repeats (20–60 repeats) were associated with PD in PD-NC patients (<i>p</i> = 0.041; OR = 3.684 (CI 1.05–13.0)) but not in PD-carriers (<i>p</i> = 0.684). The <i>C9orf72</i> 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, <i>p</i> = 0.0356). All 19 alleles within the risk-haplotype were associated with higher <i>C9orf72</i> 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 <i>C9orf72</i> in PD pathogenesis.
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