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

Emadeldin Hassanin; Zied Landoulsi; Sinthuja Pachchek; Gelani Zelimkhanov; Evi Wollscheid-Lengeling; Paul Wilmes; Liliana Vilas Boas; Carlos Vega; Michel Vaillant; Olena Tsurkalenko; Johanna Trouet; Rebecca Ting Jiin Loo; Elodie Thiry; Hermann Thien; Maud Theresine; Kate Sokolowska; Ekaterina Soboleva; Ruxandra Soare; Amir Sharify; Raquel Severino; Jens Schwamborn; Reinhard Schneider; Sabine Schmitz; Venkata Satagopam; Stefano Sapienza; Eduardo Rosales; Kirsten Roomp; Olivia Roland; Ilsé Richard; Lucie Remark; Rajesh Rawal; Armin Rauschenberger; Achilleas Pexaras; Magali Perquin; Lukas Pavelka; Laure Pauly; Claire Pauly; Clarissa P.C. Gomes; Fozia Noor; Jean Paul Nicolay; Beatrice Nicolai; Sarah Nickels; Ulf Nehrbass; Romain Nati; Maeva Munsch; Saïda Mtimet; Michel Mittelbronn; Maura Minelli; Myriam Menster; Anne Marie Hanff; NCER-PD Consortium

doi:10.1038/s41531-025-00997-y

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

Emadeldin Hassanin
, Zied Landoulsi
, Sinthuja Pachchek
, Gelani Zelimkhanov
, Evi Wollscheid-Lengeling
, Paul Wilmes
, Liliana Vilas Boas
, Carlos Vega
, Michel Vaillant
, Olena Tsurkalenko
, Johanna Trouet
, Rebecca Ting Jiin Loo
, Elodie Thiry
, Hermann Thien
, Maud Theresine
, Kate Sokolowska
, Ekaterina Soboleva
, Ruxandra Soare
, Amir Sharify
, Raquel Severino

Jens Schwamborn, Reinhard Schneider, Sabine Schmitz, Venkata Satagopam, Stefano Sapienza, Eduardo Rosales, Kirsten Roomp, Olivia Roland, Ilsé Richard, Lucie Remark, Rajesh Rawal, Armin Rauschenberger, Achilleas Pexaras, Magali Perquin, Lukas Pavelka, Laure Pauly, Claire Pauly, Clarissa P.C. Gomes, Fozia Noor, Jean Paul Nicolay, Beatrice Nicolai, Sarah Nickels, Ulf Nehrbass, Romain Nati, Maeva Munsch, Saïda Mtimet, Michel Mittelbronn, Maura Minelli, Myriam Menster, Anne Marie Hanff, NCER-PD Consortium

Research output: Contribution to journal › Article › Academic › peer-review

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<inf>PVs</inf>) 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<inf>PVs</inf> 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<inf>PVs</inf> penetrance, highlighting implications for genetic counseling and clinical trial design in GBA1-associated PD.

Original language	English
Article number	162
Number of pages	8
Journal	npj Parkinson's Disease
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41531-025-00997-y
Publication status	Published - 1 Dec 2025

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Hassanin, E., Landoulsi, Z., Pachchek, S., Zelimkhanov, G., Wollscheid-Lengeling, E., Wilmes, P., Boas, L. V., Vega, C., Vaillant, M., Tsurkalenko, O., Trouet, J., Loo, R. T. J., Thiry, E., Thien, H., Theresine, M., Sokolowska, K., Soboleva, E., Soare, R., Sharify, A., ... NCER-PD Consortium (2025). Penetrance of Parkinson’s disease in GBA1 carriers depends on variant severity and polygenic background. npj Parkinson's Disease, 11(1), Article 162. https://doi.org/10.1038/s41531-025-00997-y

@article{6f82785f21924636ab2fee3233a042e5,

title = "Penetrance of Parkinson{\textquoteright}s disease in GBA1 carriers depends on variant severity and polygenic background",

abstract = "Heterozygous GBA1 variants increase Parkinson{\textquoteright}s disease (PD) risk with variable penetrance. We investigated the interaction between genome-wide polygenic risk scores (PRS) and severity of pathogenic GBA1 variants (GBA1PVs) 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{\textquoteright}s Study, with PRS calculated using genome-wide significant SNPs. GBA1PVs 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 GBA1PVs penetrance, highlighting implications for genetic counseling and clinical trial design in GBA1-associated PD.",

author = "Emadeldin Hassanin and Zied Landoulsi and Sinthuja Pachchek and Gelani Zelimkhanov and Evi Wollscheid-Lengeling and Paul Wilmes and Boas, \{Liliana Vilas\} and Carlos Vega and Michel Vaillant and Olena Tsurkalenko and Johanna Trouet and Loo, \{Rebecca Ting Jiin\} and Elodie Thiry and Hermann Thien and Maud Theresine and Kate Sokolowska and Ekaterina Soboleva and Ruxandra Soare and Amir Sharify and Raquel Severino and Jens Schwamborn and Reinhard Schneider and Sabine Schmitz and Venkata Satagopam and Stefano Sapienza and Eduardo Rosales and Kirsten Roomp and Olivia Roland and Ils{\'e} Richard and Lucie Remark and Rajesh Rawal and Armin Rauschenberger and Achilleas Pexaras and Magali Perquin and Lukas Pavelka and Laure Pauly and Claire Pauly and Gomes, \{Clarissa P.C.\} and Fozia Noor and Nicolay, \{Jean Paul\} and Beatrice Nicolai and Sarah Nickels and Ulf Nehrbass and Romain Nati and Maeva Munsch and Sa{\"i}da Mtimet and Michel Mittelbronn and Maura Minelli and Myriam Menster and Hanff, \{Anne Marie\} and \{NCER-PD Consortium\}",

note = "Funding Information: Data used to prepare this article were obtained from the UKB, and the National Center of Excellence in Research: Early diagnosis and stratification of Parkinson\textbackslash{}u2019s Disease (NCER-PD) ( https://www.parkinson.lu/ ). This research has been conducted using the UK Biobank Resource under application number 73507. The NCER-PD is funded by the Luxembourg National Research Fund (FNR/NCER13/BM/11264123). We would like to thank all participants of the Luxembourg Parkinson\textbackslash{}u2019s Study for their important support to our research. Furthermore, we acknowledge the joint effort of the NCER-PD Consortium members from the partner institutions Luxembourg Center for Systems Biomedicine, Luxembourg Institute of Health, Center Hospitalier de Luxembourg, and Laboratoire National de Sant\textbackslash{}u00E9 generally contributing to the Luxembourg Parkinson\textbackslash{}u2019s Study as listed below in the Author Information section. Parts of the computational analysis were done on the High-Performance Computing cluster of the University of Luxembourg ( https://hpc.uni.lu/ ). The FNR supported P.M. as part of the National Center of Excellence in Research on Parkinson\textbackslash{}u2019s disease (NCER-PD, FNR11264123) and the DFG Research Units FOR2715 (INTER/DFG/17/11583046) and FOR2488 (INTER/DFG/19/14429377). The Fonds National de Recherche (FNR) supported D.R.B through the Industrial fellowship program of Luxembourg (FNR14323864). Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = dec,

day = "1",

doi = "10.1038/s41531-025-00997-y",

language = "English",

volume = "11",

journal = "npj Parkinson's Disease",

issn = "2373-8057",

publisher = "Nature Research",

number = "1",

}

Hassanin, E, Landoulsi, Z, Pachchek, S, Zelimkhanov, G, Wollscheid-Lengeling, E, Wilmes, P, Boas, LV, Vega, C, Vaillant, M, Tsurkalenko, O, Trouet, J, Loo, RTJ, Thiry, E, Thien, H, Theresine, M, Sokolowska, K, Soboleva, E, Soare, R, Sharify, A, Severino, R, Schwamborn, J, Schneider, R, Schmitz, S, Satagopam, V, Sapienza, S, Rosales, E, Roomp, K, Roland, O, Richard, I, Remark, L, Rawal, R, Rauschenberger, A, Pexaras, A, Perquin, M, Pavelka, L, Pauly, L, Pauly, C, Gomes, CPC, Noor, F, Nicolay, JP, Nicolai, B, Nickels, S, Nehrbass, U, Nati, R, Munsch, M, Mtimet, S, Mittelbronn, M, Minelli, M, Menster, M, Hanff, AM & NCER-PD Consortium 2025, 'Penetrance of Parkinson’s disease in GBA1 carriers depends on variant severity and polygenic background', npj Parkinson's Disease, vol. 11, no. 1, 162. https://doi.org/10.1038/s41531-025-00997-y

TY - JOUR

T1 - Penetrance of Parkinson’s disease in GBA1 carriers depends on variant severity and polygenic background

AU - Hassanin, Emadeldin

AU - Landoulsi, Zied

AU - Pachchek, Sinthuja

AU - Zelimkhanov, Gelani

AU - Wollscheid-Lengeling, Evi

AU - Wilmes, Paul

AU - Boas, Liliana Vilas

AU - Vega, Carlos

AU - Vaillant, Michel

AU - Tsurkalenko, Olena

AU - Trouet, Johanna

AU - Loo, Rebecca Ting Jiin

AU - Thiry, Elodie

AU - Thien, Hermann

AU - Theresine, Maud

AU - Sokolowska, Kate

AU - Soboleva, Ekaterina

AU - Soare, Ruxandra

AU - Sharify, Amir

AU - Severino, Raquel

AU - Schwamborn, Jens

AU - Schneider, Reinhard

AU - Schmitz, Sabine

AU - Satagopam, Venkata

AU - Sapienza, Stefano

AU - Rosales, Eduardo

AU - Roomp, Kirsten

AU - Roland, Olivia

AU - Richard, Ilsé

AU - Remark, Lucie

AU - Rawal, Rajesh

AU - Rauschenberger, Armin

AU - Pexaras, Achilleas

AU - Perquin, Magali

AU - Pavelka, Lukas

AU - Pauly, Laure

AU - Pauly, Claire

AU - Gomes, Clarissa P.C.

AU - Noor, Fozia

AU - Nicolay, Jean Paul

AU - Nicolai, Beatrice

AU - Nickels, Sarah

AU - Nehrbass, Ulf

AU - Nati, Romain

AU - Munsch, Maeva

AU - Mtimet, Saïda

AU - Mittelbronn, Michel

AU - Minelli, Maura

AU - Menster, Myriam

AU - Hanff, Anne Marie

AU - NCER-PD Consortium

N1 - Funding Information: Data used to prepare this article were obtained from the UKB, and the National Center of Excellence in Research: Early diagnosis and stratification of Parkinson\u2019s Disease (NCER-PD) ( https://www.parkinson.lu/ ). This research has been conducted using the UK Biobank Resource under application number 73507. The NCER-PD is funded by the Luxembourg National Research Fund (FNR/NCER13/BM/11264123). We would like to thank all participants of the Luxembourg Parkinson\u2019s Study for their important support to our research. Furthermore, we acknowledge the joint effort of the NCER-PD Consortium members from the partner institutions Luxembourg Center for Systems Biomedicine, Luxembourg Institute of Health, Center Hospitalier de Luxembourg, and Laboratoire National de Sant\u00E9 generally contributing to the Luxembourg Parkinson\u2019s Study as listed below in the Author Information section. Parts of the computational analysis were done on the High-Performance Computing cluster of the University of Luxembourg ( https://hpc.uni.lu/ ). The FNR supported P.M. as part of the National Center of Excellence in Research on Parkinson\u2019s disease (NCER-PD, FNR11264123) and the DFG Research Units FOR2715 (INTER/DFG/17/11583046) and FOR2488 (INTER/DFG/19/14429377). The Fonds National de Recherche (FNR) supported D.R.B through the Industrial fellowship program of Luxembourg (FNR14323864). Publisher Copyright: © The Author(s) 2025.

PY - 2025/12/1

Y1 - 2025/12/1

N2 - 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 (GBA1PVs) 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. GBA1PVs 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 GBA1PVs penetrance, highlighting implications for genetic counseling and clinical trial design in GBA1-associated PD.

AB - 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 (GBA1PVs) 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. GBA1PVs 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 GBA1PVs penetrance, highlighting implications for genetic counseling and clinical trial design in GBA1-associated PD.

U2 - 10.1038/s41531-025-00997-y

DO - 10.1038/s41531-025-00997-y

M3 - Article

SN - 2373-8057

VL - 11

JO - npj Parkinson's Disease

JF - npj Parkinson's Disease

IS - 1

M1 - 162

ER -

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

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