Oligogenic effects in Parkinson’s disease; the interplay of risk and protective variants affects disease risk and age-at-onset

Parkinson’s disease (PD), a motor and non-motor neurodegenerative disorder, affects up to 4% by age 80. This multifactorial disease is associated with aging, environmental and genetic factors, with more than 90 genetic disease loci identified. The most common genetic risk factors worldwide are variants within LRRK2 and GBA genes, which are also the major variations observed in PD patients of Ashkenazi origin (AJ). We characterized the world largest cohort of consecutively recruited AJ-PDs (>1200) and used molecular genotyping tools to understand the complex genetic basis of PD. More than a third of the patients carried mutations in LRRK2 (G2019S), GBA (10 mutations) and the lysosomal SMPD1 (L302P). In a substantial percentage of carrier patients (11%) more than 1 mutation was detected, suggesting an oligogenic phenomenon. This was further supported by the fact that 35% of patients carrying the non-Gaucher GBA mutations (E326K, T369M), carried additional mutation. Moreover, a wide range of individual allelic odds ratios was observed (1.86-12.84), with an additive effect on risk and age-at-disease-onset in patients carrying 2 mutations (in LRRK2 and GBA) compared to carriers of 1 mutation. In addition, whole-genome-sequencing (WGS) was performed in 340 patients and controls. CADD and EIGEN analyses of all coding and non-coding variants in PARK16 locus identified a transcriptional-modifier-protective variant that was further genotyped in our cohorts. Stratification analysis revealed a gene-specific effect on LRRK2-PD and not on GBA-PD. Our data demonstrate the need for oligogenic approach and WGS analysis in PD to determine the interplay between risk and protective alleles.