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

Zied Landoulsi; Gelani Zelimkhanov; Carlos Vega; Michel Vaillant; Olena Tsurkalenko; Johanna Trouet; Hermann Thien; Maud Theresine; Kate Sokolowska; Amir Sharify; Stefano Sapienza; Olivia Roland; Ilsé Richard; Lucie Remark; Armin Rauschenberger; Achilleas Pexaras; Magali Perquin; Lukas Pavelka; Laure Pauly; Claire Pauly; Fozia Noor; Sarah Nickels; Ulf Nehrbass; Maeva Munsch; Saïda Mtimet; Michel Mittelbronn; Myriam Menster; Alexia Mendibide; Chouaib Mediouni; Deborah Mcintyre; Guilherme Marques; Tainá M. Marques; Victoria Lorentz; Ana Festas Lopes; Pauline Lambert; Olga Kofanova; Jochen Klucken; Sonja Jónsdóttir; Alexander Hundt; Margaux Henry; Estelle Henry; Anne Marie Hanff; Jérôme Graas; Marijus Giraitis; Laura Georges; Manon Gantenbein; Carlos Gamio; Joëlle Fritz; Angelo Ferrari; Nancy De Bremaeker; Gessica Contesotto; Ibrahim Boussaad; Guy Berchem; Sibylle Béchet; Katy Beaumont; Roxane Batutu; Myriam Alexandre; Gloria Aguayo; Geeta Acharya; Rejko Krüger; 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

Zied Landoulsi, Gelani Zelimkhanov, Carlos Vega, Michel Vaillant, Olena Tsurkalenko, Johanna Trouet, Hermann Thien, Maud Theresine, Kate Sokolowska, Amir Sharify, Stefano Sapienza, Olivia Roland, Ilsé Richard, Lucie Remark, Armin Rauschenberger, Achilleas Pexaras, Magali Perquin, Lukas Pavelka, Laure Pauly, Claire PaulyFozia Noor, Sarah Nickels, Ulf Nehrbass, Maeva Munsch, Saïda Mtimet, Michel Mittelbronn, Myriam Menster, Alexia Mendibide, Chouaib Mediouni, Deborah Mcintyre, Guilherme Marques, Tainá M. Marques, Victoria Lorentz, Ana Festas Lopes, Pauline Lambert, Olga Kofanova, Jochen Klucken, Sonja Jónsdóttir, Alexander Hundt, Margaux Henry, Estelle Henry, Anne Marie Hanff, Jérôme Graas, Marijus Giraitis, Laura Georges, Manon Gantenbein, Carlos Gamio, Joëlle Fritz, Angelo Ferrari, Nancy De Bremaeker, Gessica Contesotto, Ibrahim Boussaad, Guy Berchem, Sibylle Béchet, Katy Beaumont, Roxane Batutu, Myriam Alexandre, Gloria Aguayo, Geeta Acharya, Rejko Krüger, NCER-PD Consortium

Research output: Contribution to journal › Article › Research › 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_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.

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 - 12 Jun 2025

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Landoulsi, Z., Zelimkhanov, G., Vega, C., Vaillant, M., Tsurkalenko, O., Trouet, J., Thien, H., Theresine, M., Sokolowska, K., Sharify, A., Sapienza, S., Roland, O., Richard, I., Remark, L., Rauschenberger, A., Pexaras, A., Perquin, M., Pavelka, L., Pauly, L., ... 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{d1942aaa848a41218b9910fd8f142370,

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 = "Zied Landoulsi and Gelani Zelimkhanov and Carlos Vega and Michel Vaillant and Olena Tsurkalenko and Johanna Trouet and Hermann Thien and Maud Theresine and Kate Sokolowska and Amir Sharify and Stefano Sapienza and Olivia Roland and Ils{\'e} Richard and Lucie Remark and Armin Rauschenberger and Achilleas Pexaras and Magali Perquin and Lukas Pavelka and Laure Pauly and Claire Pauly and Fozia Noor and Sarah Nickels and Ulf Nehrbass and Maeva Munsch and Sa{\"i}da Mtimet and Michel Mittelbronn and Myriam Menster and Alexia Mendibide and Chouaib Mediouni and Deborah Mcintyre and Guilherme Marques and Marques, {Tain{\'a} M.} and Victoria Lorentz and Lopes, {Ana Festas} and Pauline Lambert and Olga Kofanova and Jochen Klucken and Sonja J{\'o}nsd{\'o}ttir and Alexander Hundt and Margaux Henry and Estelle Henry and Hanff, {Anne Marie} and J{\'e}r{\^o}me Graas and Marijus Giraitis and Laura Georges and Manon Gantenbein and Carlos Gamio and Jo{\"e}lle Fritz and Angelo Ferrari and {De Bremaeker}, Nancy and Gessica Contesotto and Ibrahim Boussaad and Guy Berchem and Sibylle B{\'e}chet and Katy Beaumont and Roxane Batutu and Myriam Alexandre and Gloria Aguayo and Geeta Acharya and Rejko Kr{\"u}ger and {NCER-PD Consortium}",

note = "Funding: 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{\textquoteright}s 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{\'e} generally contributing to the Luxembourg Parkinson{\textquoteright}s 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{\textquoteright}s 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 = jun,

day = "12",

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

language = "English",

volume = "11",

journal = "npj Parkinson's Disease",

issn = "2373-8057",

publisher = "Springer Nature",

number = "1",

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Landoulsi, Z, Zelimkhanov, G, Vega, C , Vaillant, M, Tsurkalenko, O, Trouet, J , Thien, H , Theresine, M, Sokolowska, K, Sharify, A, Sapienza, S, Roland, O, Richard, I, Remark, L , Rauschenberger, A , Pexaras, A , Perquin, M , Pavelka, L, Pauly, L, Pauly, C , Noor, F, Nickels, S, Nehrbass, U, Munsch, M , Mtimet, S, Mittelbronn, M, Menster, M, Mendibide, A, Mediouni, C, Mcintyre, D, Marques, G, Marques, TM, Lorentz, V , Lopes, AF , Lambert, P , Kofanova, O, Klucken, J, Jónsdóttir, S , Hundt, A, Henry, M, Henry, E , Hanff, AM , Graas, J , Giraitis, M , Georges, L , Gantenbein, M , Gamio, C , Fritz, J , Ferrari, A, De Bremaeker, N, Contesotto, G , Boussaad, I , Berchem, G , Béchet, S , Beaumont, K, Batutu, R, Alexandre, M , Aguayo, G , Acharya, G , Krüger, R & 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 - Landoulsi, Zied

AU - Zelimkhanov, Gelani

AU - Vega, Carlos

AU - Vaillant, Michel

AU - Tsurkalenko, Olena

AU - Trouet, Johanna

AU - Thien, Hermann

AU - Theresine, Maud

AU - Sokolowska, Kate

AU - Sharify, Amir

AU - Sapienza, Stefano

AU - Roland, Olivia

AU - Richard, Ilsé

AU - Remark, Lucie

AU - Rauschenberger, Armin

AU - Pexaras, Achilleas

AU - Perquin, Magali

AU - Pavelka, Lukas

AU - Pauly, Laure

AU - Pauly, Claire

AU - Noor, Fozia

AU - Nickels, Sarah

AU - Nehrbass, Ulf

AU - Munsch, Maeva

AU - Mtimet, Saïda

AU - Mittelbronn, Michel

AU - Menster, Myriam

AU - Mendibide, Alexia

AU - Mediouni, Chouaib

AU - Mcintyre, Deborah

AU - Marques, Guilherme

AU - Marques, Tainá M.

AU - Lorentz, Victoria

AU - Lopes, Ana Festas

AU - Lambert, Pauline

AU - Kofanova, Olga

AU - Klucken, Jochen

AU - Jónsdóttir, Sonja

AU - Hundt, Alexander

AU - Henry, Margaux

AU - Henry, Estelle

AU - Hanff, Anne Marie

AU - Graas, Jérôme

AU - Giraitis, Marijus

AU - Georges, Laura

AU - Gantenbein, Manon

AU - Gamio, Carlos

AU - Fritz, Joëlle

AU - Ferrari, Angelo

AU - De Bremaeker, Nancy

AU - Contesotto, Gessica

AU - Boussaad, Ibrahim

AU - Berchem, Guy

AU - Béchet, Sibylle

AU - Beaumont, Katy

AU - Batutu, Roxane

AU - Alexandre, Myriam

AU - Aguayo, Gloria

AU - Acharya, Geeta

AU - Krüger, Rejko

AU - NCER-PD Consortium

N1 - Funding: 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’s 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 Santé generally contributing to the Luxembourg Parkinson’s 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’s 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 - 2025/6/12

Y1 - 2025/6/12

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.

UR - http://www.scopus.com/inward/record.url?scp=105008567692&partnerID=8YFLogxK

UR - https://pubmed.ncbi.nlm.nih.gov/40506446/

U2 - 10.1038/s41531-025-00997-y

DO - 10.1038/s41531-025-00997-y

M3 - Article

C2 - 40506446

AN - SCOPUS:105008567692

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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