Trio approach reveals higher risk of PD in carriers of severe vs. mild GBA mutations.

Heterozygote GBA (glucosylceramidase beta) mutations increase the risk of Parkinson's disease (PD). Data based on the measured frequencies of GBA mutated alleles in the healthy population suggest that severe GBA mutations are associated with even higher risk for PD. These data, however, are prone to methodological biases resulting from the rarity of severe mutations and from ethnic-dependent differences in allele frequencies. To overcome these biases, we traced 13 Gaucher disease (GD) patients who were compound heterozygotes for one mild (N370S) and one severe GBA mutation and who reported a parent with PD. We determined the GBA mutation status of all parents and examined them whenever possible. While 50% of the parents carried a mild GBA mutation, we hypothesized that PD cases would be more likely to carry a severe mutation. We found that 10/13 PD parents had a severe mutation and only 3/10 carried a mild mutation (binomial test P<0.05). Using an unbiased methodology, we show that carriers of severe GBA mutations are at higher risk for PD relative to carriers of the mild mutations.