Penetrance of Parkinson's disease in GBA1 carriers depends on variant severity and polygenic background

Abstract

Heterozygous GBA1 variants increase Parkinson's disease (PD) risk with variable penetrance. We investigated the interaction between genome-wide polygenic risk scores (PRS) and severity of pathogenic GBA1 variants (GBA1_PVs) to assess their combined impact on PD risk. GBA1 variants were identified from whole exome sequencing in the UK Biobank and targeted PacBio sequencing in the Luxembourg Parkinson's Study, with PRS calculated using genome-wide significant SNPs. GBA1_PVs were present in 8.8% of PD patients in the UK Biobank and 9.9% in LuxPark, with carriers showing consistently higher PD risk across all PRS categories. In the highest PRS category, PD risk increased 2.3-fold in the UK Biobank and 1.6-fold in LuxPark. Severe and mild GBA1 variants conferred nearly double the risk of PD compared to risk variants. Our findings demonstrate the impact of PRS on GBA1_PVs penetrance, highlighting implications for genetic counseling and clinical trial design in GBA1-associated PD.

Fig. 1. Parkinson’s disease (PD) risk stratified by GBA1 carrier status and polygenic risk scores (PRS) categories.

Odds ratio for PD were estimated using logistic models, while conditioning on the sex, age at assessment and the first four ancestry principal components in both UK Biobank (A) and the Luxembourg Parkinson’s Study (B). Non-carriers with intermediate PRS served as the reference group. Carriers and non-carriers were categorized into categories based on their PRS.

Fig. 2. Cumulative incidence of Parkinson’s disease (PD) stratified by GBA1 carrier status and polygenic risk scores categories in the UK Biobank.

Cumulative incidence was estimated using Cox proportional hazards models, adjusted for sex and the first four ancestry principal components. Participants were stratified by GBA1 carrier status as well as by PRS categories, in the UK Biobank. Red lines indicate GBA1 carriers and green lines indicate non-carriers. Line styles represent PRS categories, with solid lines for high PRS, dashed lines for intermediate PRS, and dotted lines for low PRS.

Fig. 3. Parkinson’s disease (PD) risk stratified by severity status of GBA1 carrier and polygenic risk score (PRS) categories.

Odds ratio (OR) for PD were estimated using logistic models, while conditioning on the sex, age at assessment and the first four ancestry principal components in both UK Biobank (A) and the Luxembourg Parkinson’s Study (B). Non-carriers with intermediate PRS served as the reference group.