Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia

Abstract

Parkinson’s disease is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of Parkinson’s disease, and currently 90 independent risk variants have been identified by genome-wide association studies. Thus far, a number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability across a spectrum of frequency and effect, from rare, highly penetrant variants to common risk alleles with small effect sizes. Variants in GBA, encoding the enzyme glucocerebrosidase, are associated with Lewy body diseases such as Parkinson’s disease and Lewy body dementia. These variants, which reduce or abolish enzymatic activity, confer a spectrum of disease risk, from 1.4- to >10-fold. An outstanding question in the field is what other genetic factors that influence GBA-associated risk for disease, and whether these overlap with known Parkinson’s disease risk variants. Using multiple, large case-control datasets, totalling 217 165 individuals (22 757 Parkinson’s disease cases, 13 431 Parkinson’s disease proxy cases, 622 Lewy body dementia cases and 180 355 controls), we identified 1691 Parkinson’s disease cases, 81 Lewy body dementia cases, 711 proxy cases and 7624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent Parkinson’s disease-associated genetic risk score to detect genetic influences on GBA risk and age at onset. We attempted to replicate our findings in two independent datasets, including the personal genetics company 23andMe, Inc. and whole-genome sequencing data. Our analysis showed that the overall Parkinson’s disease genetic risk score modifies risk for disease and decreases age at onset in carriers of GBA variants. Notably, this effect was consistent across all tested GBA risk variants. Dissecting this signal demonstrated that variants in close proximity to SNCA and CTSB (encoding cathepsin B) are the most significant contributors. Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB. Additional analyses suggest a possible genetic interaction between GBA and CTSB and GBA p.N370S induced pluripotent cell-derived neurons were shown to have decreased cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA-associated Parkinson’s disease risk and age at onset, although the total contribution of common genetics variants is not large. We further demonstrate that common variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease. Further, these results have implications for selection of GBA carriers for therapeutic interventions.

“LRRK2: Autophagy and Lysosomal Activity”

“…Two recent studies independently showed that GBA mutation carriers can also carry the LRRK2-G2019S mutation, with no impact on age of onset (Yahalom et al, 2019;Blauwendraat et al, 2020). However, when compared to non-carriers, LRRK2-G2019S carriers displayed higher activity levels of GCase, the lysosomal membrane enzyme encoded in the GBA gene that cleaves the glycolipid glucosylceramide.…”

Association Between Glucocerebrosidase Mutations and Parkinson's Disease in Ireland

“…Based on homozygous and compound heterozygous mutations resulting in specific subtypes of Gaucher's disease, GBA mutations can be classified as "mild" (p.N370S and p.R496H) and "severe" [p.L444P, p.D380A, p.R131C, p.D409H, p.R463C, p.R257Q, p.V394L, c.1263-1317del, and RecNciI-a recombinant allele (p.L444P-A456P-V460V)] (10). Carriers of mild mutations are reported to have 2.2-fold higher risk of PD and mean age at onset of 58.1 (±10.6), while carriers of severe mutations have 9.92-to 21.29-fold increased risk of PD and mean age at onset of 52.1 (±11.2) (10,11). GBA p.E326K homozygous and compound heterozygous mutations do not cause Gaucher's disease; thus, there may be a distinct mechanism predisposing to PD in carriers of p.E326K.…”

“…GBA p.E326K homozygous and compound heterozygous mutations do not cause Gaucher's disease; thus, there may be a distinct mechanism predisposing to PD in carriers of p.E326K. Until recently, believed to be a benign polymorphism, now p.E326K is an established risk factor (large meta-analyses) causing rapid motor progression of PD (β = 3.42; 95% CI, 0.66-6.17; p = 0.02) (12,13), cognitive decline, and the development of RBD among those who did not have the disorder at baseline (5,6,11). Similarly, there is an emerging trend in the literature to classify p.T369M as a risk variant (with the reported effect size similar to that of p.E326K, baseline RBD, associated cognitive decline, and higher hazard ratio of reaching H&Y3) (4,6,14,15).…”

Network Protein Interaction in Parkinson’s Disease and Periodontitis Interplay: A Preliminary Bioinformatic Analysis

“…For Parkinson’s disease, we used a summary statistics dataset from periodontitis GWAS performed in up to 1,640,901 individuals of European, Asian, American, Sub-Saharan African and other ancestries [ 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 ] ( Table S2 ). GWAS datasets for both PD and periodontitis were derived from different populations, as there are no GWAS data combining both conditions.…”