Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease

Abstract

Objectives: The objective of this study is to clarify the role of (G4C2)n expansions in the etiology of Parkinson disease (PD) in the worldwide multicenter Genetic Epidemiology of Parkinson's Disease (GEO-PD) cohort.

Methods: C9orf72 (G4C2)n repeats were assessed in a GEO-PD cohort of 7,494 patients diagnosed with PD and 5,886 neurologically healthy control individuals ascertained in Europe, Asia, North America, and Australia.

Results: A pathogenic (G4C2)n>60 expansion was detected in only 4 patients with PD (4/7,232; 0.055%), all with a positive family history of neurodegenerative dementia, amyotrophic lateral sclerosis, or atypical parkinsonism, while no carriers were detected with typical sporadic or familial PD. Meta-analysis revealed a small increase in risk of PD with an increasing number of (G4C2)n repeats; however, we could not detect a robust association between the C9orf72 (G4C2)n repeat and PD, and the population attributable risk was low.

Conclusions: Together, these findings indicate that expansions in C9orf72 do not have a major role in the pathogenesis of PD. Testing for C9orf72 repeat expansions should only be considered in patients with PD who have overt symptoms of frontotemporal lobar degeneration/amyotrophic lateral sclerosis or apparent family history of neurodegenerative dementia or motor neuron disease.

Figure 1. Overall distribution of C9orf72 repeat alleles in the GEO-PD cohorts

Only cohorts including both patients with PD and controls that were size-corrected based on the reference panel were included in the study. When the highest count for a specific allele was 5 or less across cohorts, the allele was clumped with the next allele for each cohort. (A) Allele frequencies. The p values for individual alleles were calculated using a Dersimonian-Laird random-effect meta-analysis. (B) Allele counts. *Nominally significant p values. Con = controls; GEO-PD = Genetic Epidemiology of Parkinson's Disease; PD = Parkinson disease.