C9orf72-G₄C₂ Intermediate Repeats and Parkinson's Disease; A Data-Driven Hypothesis

Area of Science:

• Neurogenetics
• Neurodegenerative diseases

Background:

• Pathogenic C9orf72 G4C2 repeat expansions are linked to ALS/FTD, but their role in Parkinson's disease (PD) is unclear.
• Intermediate repeat lengths in C9orf72 have not been definitively linked to PD risk.

Purpose of the Study:

• To investigate the potential involvement of C9orf72 repeats and associated risk-haplotypes in the pathogenesis of Parkinson's disease.
• To assess the association of C9orf72 repeat numbers and risk-haplotypes with PD in both mutation carriers and non-carriers of known PD-associated genes.

Main Methods:

• Determined C9orf72 repeat numbers using flanking and repeat-primed PCR assays.
• Assessed the C9orf72 risk-haplotype using SNP-array analysis.
• Stratified PD patient analysis into carriers (LRRK2, GBA, SMPD1 mutations) and non-carriers, comparing allelic distributions with controls.

Main Results:

• Allelic distribution of C9orf72 repeats differed significantly in PD non-carriers compared to controls (p=0.034 for higher repeat size, p=0.023 for combined repeats).
• Intermediate repeats (20-60) were associated with PD in non-carriers (OR=3.684, p=0.041) but not in carriers (p=0.684).
• The C9orf72 risk-haplotype was more frequent in PD non-carriers (OR=1.71, p=0.0356) and linked to higher C9orf72 RNA levels.

Conclusions:

• Intermediate C9orf72 repeats may represent a risk factor for PD in non-carriers.
• The risk appears influenced by both repeat number and specific genotypes within the C9orf72 risk-haplotype.
• Further studies are warranted to fully elucidate the role of C9orf72 in Parkinson's disease pathogenesis.