A large-scale full GBA1 gene screening in Parkinson’s disease in the Netherlands

Parkinson’s disease is the second most common neurodegenerative disorder, with a multifactorial disease etiology, consisting of both environmental and genetic risk factors. The most common genetic risk factors known to date are variants in the GBA (GBA1) gene, encoding for the lysosomal glucocerebrosidase enzyme. In most populations, 4-12% of Parkinson’s disease patients carry a heterozygous GBA1 variant and in Ashkenazi Jewish Parkinson’s disease patients this is approximately 20%. For Parkinson’s disease patients, Odds Ratios (OR) of having a GBA1 variant compared to people without Parkinson’s disease usually vary between 2-7. Higher ORs up to 20 have been reported for specific variants, but these are usually based on studies with a small number of carriers. Rare homozygous or compound heterozygous GBA1 variants can cause the autosomal recessive lysosomal storage disorder Gaucher’s disease. Over 300 variants have been reported associated with Gaucher’s disease and all of these alleles are potential risk-factors for developing Parkinson’s disease. Since the discovery of this relatively common risk factor in Parkinson’s disease, glucocerebrosidase, the protein encoded by this gene has become a popular target for development of a potential first disease-modifying therapy for Parkinson’s disease. 

Full GBA1 gene sequencing has previously been shown to be essential, since there can be a long tail of rare variants or even population-specific variants (Lesage, Anheim, et al., 2011; Ruskey et al., 2019; Velez-Pardo et al., 2019). Nevertheless, rarely the entire GBA1 gene has been studied in a large cohort from a single population. In order to do this, a large-scale saliva screening was performed in the Netherlands. This screening was combined with the preparation for a clinical trial, in order to identify sufficient patients with a GBA1 variant for a clinical trial with a drug that is expected to enhance glucocerebrosidase activity and hence to be disease modifying in Parkinson’s disease patients. In the current study, the  GBA1 entire open reading frame in 3402 people with Parkinson’s disease from the Netherlands has been sequenced. Family history of Parkinson’s disease was assessed in a subset of patients with the most common variants, to compare familial aggregation of Parkinson’s disease between several GBA1 variants. Ancestry was assessed to investigate a possible founder-location of the likely Dutch p.D140H+p.E326K complex allele. Variant frequency of p.E326K and p.D140H mutations, that were highly prevalent in our Dutch sample, will be compared to the UGLI control cohort.