Abstract
Background
Spinocerebellar ataxia type 3 (SCA3) is caused by CAG repeat expansion in ATXN3, which inversely correlates with age at onset but does not fully account for interindividual variability. A recent study in a mixed European/South and North American cohort suggested that the PRKN V380L variant (rs1801582), particularly in C/C homozygotes, was associated with earlier disease onset. We therefore performed a replication analysis to evaluate the frequency and potential clinical relevance of rs1801582 in a Japanese SCA3 cohort.Methods
rs1801582 genotypes were determined by Sanger sequencing in 228 genetically confirmed SCA3 patients and 260 SCA6 patients as convenience disease controls. Genotype frequencies were additionally compared with East Asian reference populations from the 1000 Genomes Project Phase 3 dataset. Associations with age at onset were evaluated using multivariable linear regression adjusted for expanded ATXN3 CAG repeat length, normal ATXN3 CAG repeat length, and sex.Results
Genotype frequencies in SCA3 (G/G: 86.0%, G/C: 13.2%, C/C: 0.9%) were similar to those in controls (G/G: 85.8%, G/C: 13.5%, C/C: 0.8%) and closely resembled those reported in East Asian reference populations. Because of the extremely small number of C/C carriers (n = 2), subsequent analyses focused on G/G and G/C carriers. In SCA3, median age at onset was comparable between genotypes (42 vs. 41 years), and median expanded ATXN3 CAG repeat lengths did not differ between groups (71 vs. 71 repeats). Multivariable regression analysis adjusting for expanded ATXN3 CAG repeat length, normal ATXN3 CAG repeat length, and sex demonstrated that rs1801582 was not independently associated with age at onset (β = - 0.42 years, p = 0.84), whereas expanded CAG repeat length remained a strong predictor (β = - 1.68 years per repeat, p Conclusions
The rs1801582 C/C genotype is extremely rare in Japan; therefore, the present cohort had limited statistical power to directly evaluate the previously proposed recessive modifier effect. No detectable association between rs1801582 genotype and age at onset was identified among G/G and G/C carriers in this Japanese cohort. These findings highlight the importance of population-specific validation and adequately powered replication studies when evaluating candidate genetic modifiers in SCA3.