Objective: We aimed to investigate whether polygenic background affects the penetrance of Parkinson’s disease (PD) among carriers of heterozygous pathogenic variants (PV) in GBA.

Background: Several rare homozygous mutations within the Glucocerebrosidase (GBA) gene were associated to lysosomal storage-disorder, whereas heterozygous mutations in GBA are known risk-factors for PD. Most disease-associated variants show incomplete penetrance, and the modifiers of disease penetrance are mainly unknown.

Method: We used genotyping and targeted GBA-gene sequencing data from a Luxembourgish case-controls cohort (660 PD cases/770 controls/100 GBA carriers) as a discovery cohort and replicated the results in the UK biobank cohort (770 PD cases/179095 controls/913 GBA carriers). To dissect the combined effect of polygenic risk scores (PRS) and GBA PV, we stratified participants based on PRS deciles, and carrier status. We then compared to which extent PRS affects PD risk based on their PV carrier status.

Results: In the discovery cohort, we observed a higher odds ratio (OR) in carriers with the highest PRS decile (OR 1. 69, 95% CI, 1.52-1.86) than carriers with the lowest PRS decile (OR 1.08, 95% CI, 0.96-1.37). Similar trend was observed in the replication cohort, the ORs in carriers of GBA PV ranged from (OR 0.87, 95% CI, 0.56-1.37) to (OR 2.38, 95% CI, 1.70-3.49) depending on PRS decile.

Conclusion: Our results show that PRS, and GBA PV contribute independently and additively to the disease risk. Our findings demonstrate that PD risk is influenced by the polygenic background in both sporadic and GBA-associated PD.

« Back to 2023 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/combined-effect-of-polygenic-background-and-gba-pathogenic-variants-in-parkinsons-disease-risk/