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[Preprint]. 2025 Jul 8:2024.08.21.24311915.
doi: 10.1101/2024.08.21.24311915.

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

Zied Landoulsi  1   2 , Ashwin Ashok Kumar Sreelatha  3 , Nicole Kuznetsov  4   5 , Claudia Schulte  6   7 , Dheeraj Reddy Bobbili  1 , Ludovica Montanucci  8 , Costin Leu  9   10 , Lisa-Marie Niestroj  11 , Emadeldin Hassanin  1 , Cloé Domenighetti  12 , Pierre-Emmanuel Sugier  12 , Milena Radivojkov-Blagojevic  13 , Peter Lichtner  13 , Berta Portugal  14 , Connor Edsall  15 , Jens Kru Ger  16 , Dena G Hernandez  15 , Cornelis Blauwendraat  15 , George D Mellick  17 , Alexander Zimprich  18 , Walter Pirker  19 , Manuela Tan  20 , Ekaterina Rogaeva  21 , Anthony Lang  21   22   23   24 , Sulev Koks  25   26 , Pille Taba  27   28 , Suzanne Lesage  29 , Alexis Brice  29 , Jean-Christophe Corvol  29   3 , Marie-Christine Chartier-Harlin  30 , Eugenie Mutez  30 , Kathrin Brockmann  6   7 , Angela B Deutschländer  31   32   33 , Georges M Hadjigeorgiou  34   35 , Efthimos Dardiotis  35 , Leonidas Stefanis  36   37 , Athina Maria Simitsi  37 , Enza Maria Valente  38   4 , Simona Petrucci  39   40 , Letizia Straniero  41 , Anna Zecchinelli  42 , Gianni Pezzoli  42   43 , Laura Brighina  44   45 , Carlo Ferrarese  44   45 , Grazia Annesi  46 , Andrea Quattrone  47 , Monica Gagliardi  48 , Lena F Burbulla  7   49   50   51 , Hirotaka Matsuo  52 , Akiyoshi Nakayama  52 , Nobutaka Hattori  53 , Kenya Nishioka  53 , Sun Ju Chung  54 , Yun Joong Kim  55 , Lukas Pavelka  2 , Pierre Kolber  56 , Bart Pc van de Warrenburg  57 , Bastiaan R Bloem  57 , Andrew B Singleton  15   4 , Dan Vitale  4   5 , Mathias Toft  58 , Lasse Pihlstrom  58 , Leonor Correia Guedes  59   60 , Joaquim J Ferreira  59   61 , Soraya Bardien  62   63 , Jonathan Carr  64 , Eduardo Tolosa  65   66 , Mario Ezquerra  67 , Pau Pastor  68   69 , Karin Wirdefeldt  70   71 , Nancy L Pedersen  71 , Caroline Ran  72 , Andrea C Belin  72 , Andreas Puschmann  73 , Carl E Clarke  74 , Karen E Morrison  75 , Dimitri Krainc  49 , Matt J Farrer  76 , Dennis Lal  8   77   78 ; Global Parkinson Genetics Program (GP2); Alexis Elbaz  12 , Thomas Gasser  6   7 , Rejko Krüger  1   2   56 , Manu Sharma  3 , Patrick May  1
Affiliations

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

Zied Landoulsi et al. medRxiv. .

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.

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Conflict of interest statement

K.B reports consulting for F. Hoffmann-La Roche Ltd. and Vanqua Bio. J.C.C served on advisory boards of Biogen, Denali, and UCB. L.S has served on advisory boards and received honoraria from AbbVie, Biogen, and Sanofi. R.K reports nonfinancial support from AbbVie and Zambon during the conduct of the study. B.R.B reports grants from UCB and AbbVie during the conduct of the study. J.J.F reports grants and personal fees from AbbVie, Biogen, Novartis, Bial, Medtronic, Teva. E.T reports consultancy honoraria from Teva, Bial, Biogen, Roche, Boehringer Ingelheim, and Prevail Therapeutics. N.H reports personal fees and other support from multiple pharmaceutical companies. T.G holds a patent (EP1802749 A2) related to the LRRK2 gene for neurodegenerative disease diagnosis and therapy. M.S serves on the scientific advisory board of Vanqua Bio. All other authors: nothing to report.

Figures

Figure 1:
Figure 1:. Overview of the study:
schematic representation of the analysis workflow Study design.
Figure 2:
Figure 2:. Genome-wide meta-analysis of PD.
Miami plot of the CNV genome-wide association analyses illustrating the −log10 transformed Bonferroni-corrected p-values (DEL and DUP for deletions at the top and duplications at the bottom, mirrored respectively) for the enrichment of CNVs in cases vs. controls for each 200 kb sliding window. Results are shown for Fisher’s exact tests (A) and logistic regression before (B) and after (C) the exclusion of 220 samples from the Tübingen cohort carrying genome-wide significant CNVs, Adjacent chromosomes are shown in alternating light and dark colors. Genomic regions that exceeded the Bonferroni-corrected significance threshold (blue line, α =3.74×10−6) were annotated with the genomic band containing the signal.
Figure 3:
Figure 3:. Genome-wide meta-analysis of EOPD.
Miami plot of the CNV genome-wide association analyses illustrating the −log10 transformed Bonferroni-corrected p-values (DEL and DUP for deletions at the top and duplications at the bottom, mirrored respectively) of the Fisher’s exact tests for the enrichment of CNVs in cases vs. controls for each 200 kb sliding window before (A) and after (B) the exclusion of 220 samples from the Tübingen cohort carrying genome-wide significant CNVs. Adjacent chromosomes are shown in alternating light and dark colors. Genomic regions that exceeded the Bonferroni-corrected significance threshold (blue line, α =3.74×10−6) were annotated with the genomic band containing the signal.
Figure 4:
Figure 4:. Rare CNV burden in PD and Early-onset PD patients compared to controls for different categories.
A. Logistic regression was used to calculate odds ratios (ORs) and Bonferroni-adjusted p-values for each CNV category, and were adjusted for age, sex, and the first five components of PCAs. Protein-coding gene categories were defined as all coding genes except PD-related genes. * Bonferroni adjusted p-values surpassing the multiple testing cut-off. B-C. Kaplan–Meier estimates of individuals (PD patients and controls in B and PD patients only in C) carrying a CNV in a PD-related gene and individuals with other or no CNVs. Probability: the probability of not having PD symptoms. Age: age at last visit for controls or age at onset for cases. Highlighting around curves indicates 95% confidence intervals.
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