Genome-wide association study of copy number variations in Parkinson's disease

Zied Landoulsi; Ashwin Ashok Kumar Sreelatha; Nicole Kuznetsov; Claudia Schulte; Dheeraj Reddy Bobbili; Ludovica Montanucci; Costin Leu; Lisa-Marie Niestroj; Emadeldin Hassanin; Cloé Domenighetti; Pierre-Emmanuel Sugier; Milena Radivojkov-Blagojevic; Peter Lichtner; Berta Portugal; Connor Edsall; Jens Kru Ger; Dena G Hernandez; Cornelis Blauwendraat; George D Mellick; Alexander Zimprich; Walter Pirker; Manuela Tan; Ekaterina Rogaeva; Anthony Lang; Sulev Koks; Pille Taba; Suzanne Lesage; Alexis Brice; Jean-Christophe Corvol; Marie-Christine Chartier-Harlin; Eugenie Mutez; Kathrin Brockmann; Angela B Deutschländer; Georges M Hadjigeorgiou; Efthimos Dardiotis; Leonidas Stefanis; Athina Maria Simitsi; Enza Maria Valente; Simona Petrucci; Letizia Straniero; Anna Zecchinelli; Gianni Pezzoli; Laura Brighina; Carlo Ferrarese; Grazia Annesi; Andrea Quattrone; Monica Gagliardi; Lena F Burbulla; Hirotaka Matsuo; Karen E Morrison; Global Parkinson Genetics Program (GP2)

Genome-wide association study of copy number variations in Parkinson's disease

Zied Landoulsi, Ashwin Ashok Kumar Sreelatha, Nicole Kuznetsov, Claudia Schulte, Dheeraj Reddy Bobbili, Ludovica Montanucci, Costin Leu, Lisa-Marie Niestroj, Emadeldin Hassanin, Cloé Domenighetti, Pierre-Emmanuel Sugier, Milena Radivojkov-Blagojevic, Peter Lichtner, Berta Portugal, Connor Edsall, Jens Kru Ger, Dena G Hernandez, Cornelis Blauwendraat, George D Mellick, Alexander ZimprichWalter Pirker, Manuela Tan, Ekaterina Rogaeva, Anthony Lang, Sulev Koks, Pille Taba, Suzanne Lesage, Alexis Brice, Jean-Christophe Corvol, Marie-Christine Chartier-Harlin, Eugenie Mutez, Kathrin Brockmann, Angela B Deutschländer, Georges M Hadjigeorgiou, Efthimos Dardiotis, Leonidas Stefanis, Athina Maria Simitsi, Enza Maria Valente, Simona Petrucci, Letizia Straniero, Anna Zecchinelli, Gianni Pezzoli, Laura Brighina, Carlo Ferrarese, Grazia Annesi, Andrea Quattrone, Monica Gagliardi, Lena F Burbulla, Hirotaka Matsuo, Karen E Morrison, Global Parkinson Genetics Program (GP2)

School of Medicine, Dentistry and Biomedical Sciences

Research output: Working paper

7 Downloads (Pure)

Abstract

OBJECTIVE: To investigate the impact of copy number variations (CNVs) on Parkinson's disease (PD) pathogenesis using genome-wide data and explore their role in sporadic PD.

METHODS: We analyzed CNV data from 11,035 PD patients (including 2,731 early-onset PD (EOPD)) and 8,901 controls from the COURAGE-PD consortium using a sliding window CNV-GWAS and genome-wide burden analysis. The independent dataset from the Global Parkinson Genetics Program (GP2) consisted of 23,089 cases and 18,824 controls were used to validate our initial findings.

RESULTS: The exploratory dataset identifies multiple CNV regions associated with PD risk. The nominated CNV loci were not confirmed in an independent dataset, except that only a deletion in the PRKN gene, a well-established EOPD locus, remained genome-wide significant and robustly supported. CNV burden analysis showed a higher prevalence of CNVs in PD-related genes in patients compared to controls (OR=1.56 [1.18-2.09], p=0.0013), with PRKN showing the highest burden (OR=1.47 [1.10-1.98], p=0.026). Patients with CNVs in PRKN had an earlier disease onset. Burden analysis with controls and EOPD patients showed similar results.

INTERPRETATION: The largest CNV-based GWAS on PD highlights both the promise and pitfalls of array-based CNV detection in PD and underscores the relevance of whole-genome sequencing approaches in resolving the role of CNV in PD. The array-based findings are prone towards false positive findings that might arise either from platform limitations and/or cohort biases. Future studies require improved genotyping resolution and rigorous cross-cohort validation to reliably assess CNV contributions to PD risk.

Original language	English
Number of pages	33
Publication status	Published - 08 Jul 2025

Access to Document

Genome-wide association study of copy number variations in Parkinson's disease
Copyright 2025 the authors. This is published under a Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits distribution and reproduction for non-commercial purposes, provided the author and source are cited.
Other version, 827 KBLicence: CC BY-NC-ND

Cite this

Landoulsi, Z., Sreelatha, A. A. K., Kuznetsov, N., Schulte, C., Bobbili, D. R., Montanucci, L., Leu, C., Niestroj, L.-M., Hassanin, E., Domenighetti, C., Sugier, P.-E., Radivojkov-Blagojevic, M., Lichtner, P., Portugal, B., Edsall, C., Kru Ger, J., Hernandez, D. G., Blauwendraat, C., Mellick, G. D., ... Global Parkinson Genetics Program (GP2) (2025). Genome-wide association study of copy number variations in Parkinson's disease.

@techreport{f72a12e8f71541328efa740ef61a9477,

title = "Genome-wide association study of copy number variations in Parkinson's disease",

abstract = "OBJECTIVE: To investigate the impact of copy number variations (CNVs) on Parkinson's disease (PD) pathogenesis using genome-wide data and explore their role in sporadic PD.METHODS: We analyzed CNV data from 11,035 PD patients (including 2,731 early-onset PD (EOPD)) and 8,901 controls from the COURAGE-PD consortium using a sliding window CNV-GWAS and genome-wide burden analysis. The independent dataset from the Global Parkinson Genetics Program (GP2) consisted of 23,089 cases and 18,824 controls were used to validate our initial findings.RESULTS: The exploratory dataset identifies multiple CNV regions associated with PD risk. The nominated CNV loci were not confirmed in an independent dataset, except that only a deletion in the PRKN gene, a well-established EOPD locus, remained genome-wide significant and robustly supported. CNV burden analysis showed a higher prevalence of CNVs in PD-related genes in patients compared to controls (OR=1.56 [1.18-2.09], p=0.0013), with PRKN showing the highest burden (OR=1.47 [1.10-1.98], p=0.026). Patients with CNVs in PRKN had an earlier disease onset. Burden analysis with controls and EOPD patients showed similar results.INTERPRETATION: The largest CNV-based GWAS on PD highlights both the promise and pitfalls of array-based CNV detection in PD and underscores the relevance of whole-genome sequencing approaches in resolving the role of CNV in PD. The array-based findings are prone towards false positive findings that might arise either from platform limitations and/or cohort biases. Future studies require improved genotyping resolution and rigorous cross-cohort validation to reliably assess CNV contributions to PD risk.",

author = "Zied Landoulsi and Sreelatha, \{Ashwin Ashok Kumar\} and Nicole Kuznetsov and Claudia Schulte and Bobbili, \{Dheeraj Reddy\} and Ludovica Montanucci and Costin Leu and Lisa-Marie Niestroj and Emadeldin Hassanin and Clo{\'e} Domenighetti and Pierre-Emmanuel Sugier and Milena Radivojkov-Blagojevic and Peter Lichtner and Berta Portugal and Connor Edsall and \{Kru Ger\}, Jens and Hernandez, \{Dena G\} and Cornelis Blauwendraat and Mellick, \{George D\} and Alexander Zimprich and Walter Pirker and Manuela Tan and Ekaterina Rogaeva and Anthony Lang and Sulev Koks and Pille Taba and Suzanne Lesage and Alexis Brice and Jean-Christophe Corvol and Marie-Christine Chartier-Harlin and Eugenie Mutez and Kathrin Brockmann and Deutschl{\"a}nder, \{Angela B\} and Hadjigeorgiou, \{Georges M\} and Efthimos Dardiotis and Leonidas Stefanis and Simitsi, \{Athina Maria\} and Valente, \{Enza Maria\} and Simona Petrucci and Letizia Straniero and Anna Zecchinelli and Gianni Pezzoli and Laura Brighina and Carlo Ferrarese and Grazia Annesi and Andrea Quattrone and Monica Gagliardi and Burbulla, \{Lena F\} and Hirotaka Matsuo and Morrison, \{Karen E\} and \{Global Parkinson Genetics Program (GP2)\}",

year = "2025",

month = jul,

day = "8",

language = "English",

type = "WorkingPaper",

}

Landoulsi, Z, Sreelatha, AAK, Kuznetsov, N, Schulte, C, Bobbili, DR, Montanucci, L, Leu, C, Niestroj, L-M, Hassanin, E, Domenighetti, C, Sugier, P-E, Radivojkov-Blagojevic, M, Lichtner, P, Portugal, B, Edsall, C, Kru Ger, J, Hernandez, DG, Blauwendraat, C, Mellick, GD, Zimprich, A, Pirker, W, Tan, M, Rogaeva, E, Lang, A, Koks, S, Taba, P, Lesage, S, Brice, A, Corvol, J-C, Chartier-Harlin, M-C, Mutez, E, Brockmann, K, Deutschländer, AB, Hadjigeorgiou, GM, Dardiotis, E, Stefanis, L, Simitsi, AM, Valente, EM, Petrucci, S, Straniero, L, Zecchinelli, A, Pezzoli, G, Brighina, L, Ferrarese, C, Annesi, G, Quattrone, A, Gagliardi, M, Burbulla, LF, Matsuo, H, Morrison, KE & Global Parkinson Genetics Program (GP2) 2025 'Genome-wide association study of copy number variations in Parkinson's disease'.

TY - UNPB

T1 - Genome-wide association study of copy number variations in Parkinson's disease

AU - Landoulsi, Zied

AU - Sreelatha, Ashwin Ashok Kumar

AU - Kuznetsov, Nicole

AU - Schulte, Claudia

AU - Bobbili, Dheeraj Reddy

AU - Montanucci, Ludovica

AU - Leu, Costin

AU - Niestroj, Lisa-Marie

AU - Hassanin, Emadeldin

AU - Domenighetti, Cloé

AU - Sugier, Pierre-Emmanuel

AU - Radivojkov-Blagojevic, Milena

AU - Lichtner, Peter

AU - Portugal, Berta

AU - Edsall, Connor

AU - Kru Ger, Jens

AU - Hernandez, Dena G

AU - Blauwendraat, Cornelis

AU - Mellick, George D

AU - Zimprich, Alexander

AU - Pirker, Walter

AU - Tan, Manuela

AU - Rogaeva, Ekaterina

AU - Lang, Anthony

AU - Koks, Sulev

AU - Taba, Pille

AU - Lesage, Suzanne

AU - Brice, Alexis

AU - Corvol, Jean-Christophe

AU - Chartier-Harlin, Marie-Christine

AU - Mutez, Eugenie

AU - Brockmann, Kathrin

AU - Deutschländer, Angela B

AU - Hadjigeorgiou, Georges M

AU - Dardiotis, Efthimos

AU - Stefanis, Leonidas

AU - Simitsi, Athina Maria

AU - Valente, Enza Maria

AU - Petrucci, Simona

AU - Straniero, Letizia

AU - Zecchinelli, Anna

AU - Pezzoli, Gianni

AU - Brighina, Laura

AU - Ferrarese, Carlo

AU - Annesi, Grazia

AU - Quattrone, Andrea

AU - Gagliardi, Monica

AU - Burbulla, Lena F

AU - Matsuo, Hirotaka

AU - Morrison, Karen E

AU - Global Parkinson Genetics Program (GP2)

PY - 2025/7/8

Y1 - 2025/7/8

N2 - OBJECTIVE: To investigate the impact of copy number variations (CNVs) on Parkinson's disease (PD) pathogenesis using genome-wide data and explore their role in sporadic PD.METHODS: We analyzed CNV data from 11,035 PD patients (including 2,731 early-onset PD (EOPD)) and 8,901 controls from the COURAGE-PD consortium using a sliding window CNV-GWAS and genome-wide burden analysis. The independent dataset from the Global Parkinson Genetics Program (GP2) consisted of 23,089 cases and 18,824 controls were used to validate our initial findings.RESULTS: The exploratory dataset identifies multiple CNV regions associated with PD risk. The nominated CNV loci were not confirmed in an independent dataset, except that only a deletion in the PRKN gene, a well-established EOPD locus, remained genome-wide significant and robustly supported. CNV burden analysis showed a higher prevalence of CNVs in PD-related genes in patients compared to controls (OR=1.56 [1.18-2.09], p=0.0013), with PRKN showing the highest burden (OR=1.47 [1.10-1.98], p=0.026). Patients with CNVs in PRKN had an earlier disease onset. Burden analysis with controls and EOPD patients showed similar results.INTERPRETATION: The largest CNV-based GWAS on PD highlights both the promise and pitfalls of array-based CNV detection in PD and underscores the relevance of whole-genome sequencing approaches in resolving the role of CNV in PD. The array-based findings are prone towards false positive findings that might arise either from platform limitations and/or cohort biases. Future studies require improved genotyping resolution and rigorous cross-cohort validation to reliably assess CNV contributions to PD risk.

AB - OBJECTIVE: To investigate the impact of copy number variations (CNVs) on Parkinson's disease (PD) pathogenesis using genome-wide data and explore their role in sporadic PD.METHODS: We analyzed CNV data from 11,035 PD patients (including 2,731 early-onset PD (EOPD)) and 8,901 controls from the COURAGE-PD consortium using a sliding window CNV-GWAS and genome-wide burden analysis. The independent dataset from the Global Parkinson Genetics Program (GP2) consisted of 23,089 cases and 18,824 controls were used to validate our initial findings.RESULTS: The exploratory dataset identifies multiple CNV regions associated with PD risk. The nominated CNV loci were not confirmed in an independent dataset, except that only a deletion in the PRKN gene, a well-established EOPD locus, remained genome-wide significant and robustly supported. CNV burden analysis showed a higher prevalence of CNVs in PD-related genes in patients compared to controls (OR=1.56 [1.18-2.09], p=0.0013), with PRKN showing the highest burden (OR=1.47 [1.10-1.98], p=0.026). Patients with CNVs in PRKN had an earlier disease onset. Burden analysis with controls and EOPD patients showed similar results.INTERPRETATION: The largest CNV-based GWAS on PD highlights both the promise and pitfalls of array-based CNV detection in PD and underscores the relevance of whole-genome sequencing approaches in resolving the role of CNV in PD. The array-based findings are prone towards false positive findings that might arise either from platform limitations and/or cohort biases. Future studies require improved genotyping resolution and rigorous cross-cohort validation to reliably assess CNV contributions to PD risk.

M3 - Working paper

C2 - 39228715

BT - Genome-wide association study of copy number variations in Parkinson's disease

ER -

Genome-wide association study of copy number variations in Parkinson's disease

Abstract

Access to Document

Fingerprint

Cite this