Association between C9orf72 G4C2 repeat length and idiopathic Parkinson's disease in a Turkish cohort

Intermediate C9orf72 G4C2 repeat lengths have been proposed as potential modifiers of Parkinson's disease susceptibility; however, reported associations vary across populations and have not been evaluated in Turkish patients.

This case-control study included 136 patients with idiopathic Parkinson's disease (PD) and 100 neurologically healthy controls from Türkiye. C9orf72 G4C2 repeat length was assessed by fragment length analysis and repeat-primed PCR. A prespecified, population-informed ≥ 8-repeat threshold, derived from prior haplotype evidence, was evaluated together with a local sensitivity analysis across ≥ 6-≥10 repeats.

No participant carried a pathogenic C9orf72 expansion (≥ 30 repeats). Repeat counts ranged from 2 to 13 in patients and 2 to 10 in controls. The overall repeat-length distribution did not differ between groups (p = 0.126), whereas the three-category genotype distribution differed between groups (p = 0.033). Carriers of at least one allele with ≥ 8 repeats were more frequent among patients than controls (32/136 [23.5%] vs. 12/100 [12.0%]; OR 2.256, 95% CI 1.097-4.643; p = 0.038). Across the ≥ 6-≥10 sensitivity window, point estimates remained above unity, although 95% confidence intervals excluded unity only at ≥ 7 and ≥ 8.

A prespecified but exploratory ≥ 8-repeat carrier analysis showed higher odds of idiopathic PD, with a similar carrier signal observed at the adjacent ≥ 7 threshold. Together with the non-significant findings from the overall repeat-length distribution and continuous repeat-number analyses, these findings suggest a preliminary, threshold-sensitive susceptibility signal rather than a discrete PD-specific cutoff. Replication in larger independent cohorts with haplotype analysis, broader PD gene screening, and functional investigation is required.