Reference : Genome-wide Association and Meta-analysis of Age-at-Onset in Parkinson Disease: Evide...
Scientific journals : Article
Life sciences : Genetics & genetic processes
Human health sciences : Neurology
Systems Biomedicine
http://hdl.handle.net/10993/51393
Genome-wide Association and Meta-analysis of Age-at-Onset in Parkinson Disease: Evidence From COURAGE-PD Consortium 10.1212/WNL.0000000000200699
English
Grover, Sandeep [> >]
Ashwin, Ashok Kumar Sreelatha [> >]
Pihlstrom, Lasse [> >]
Domenighetti, Cloé [> >]
Schulte, Claudia [> >]
Sugier, Pierre-Emmanuel [> >]
Radivojkov-Blagojevic, Milena [> >]
Lichtner, Peter [> >]
Mohamed, Océane [> >]
Portugal, Berta [> >]
Landoulsi, Zied mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core]
May, Patrick mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core]
Bobbili, Dheeraj Reddy mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core]
Edsall, Connor [> >]
Bartusch, Felix [> >]
Hanussek, Maximilian [> >]
Krüger, Jens [> >]
Hernandez, Dena G. [> >]
Blauwendraat, Cornelis [> >]
Mellick, George D. [> >]
Zimprich, Alexander [> >]
Pirker, Walter [> >]
Tan, Manuela [> >]
Rogaeva, Ekaterina [> >]
Lang, Anthony [> >]
Koks, Sulev [> >]
Taba, Pille [> >]
Lesage, Suzanne [> >]
Brice, Alexis [> >]
Corvol, Jean-Christophe [> >]
Chartier-Harlin, Marie-Christine [> >]
Mutez, Eugenie [> >]
Brockmann, Kathrin [> >]
Deutschländer, Angela B. [> >]
Hadjigeorgiou, Georges M. [> >]
Dardiotis, Efthimos [> >]
Stefanis, Leonidas [> >]
Simitsi, Athina Maria [> >]
Valente, Enza Maria [> >]
Petrucci, Simona [> >]
Straniero, Letizia [> >]
Zecchinelli, Anna [> >]
Pezzoli, Gianni [> >]
Brighina, Laura [> >]
Ferrarese, Carlo [> >]
Annesi, Grazia [> >]
Quattrone, Andrea [> >]
Gagliardi, Monica [> >]
Burbulla, Lena F. [> >]
Matsuo, Hirotaka [> >]
Kawamura, Yusuke [> >]
Hattori, Nobutaka [> >]
Nishioka, Kenya [> >]
Chung, Sun Ju [> >]
Kim, Yun Joong [> >]
Pavelka, Lukas mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience]
van de Warrenburg, Bart P. C. [> >]
Bloem, Bastiaan R. [> >]
Singleton, Andrew B. [> >]
Aasly, Jan [> >]
Toft, Mathias [> >]
Guedes, Leonor Correia [> >]
Ferreira, Joaquim J. [> >]
Bardien, Soraya [> >]
Carr, Jonathan [> >]
Tolosa, Eduardo [> >]
Ezquerra, Mario [> >]
Pastor, Pau [> >]
Diez-Fairen, Monica [> >]
Wirdefeldt, Karin [> >]
Pedersen, Nancy L. [> >]
Ran, Caroline [> >]
Belin, Andrea C. [> >]
Puschmann, Andreas [> >]
Hellberg, Clara [> >]
Clarke, Carl E. [> >]
Morrison, Karen E. [> >]
Krainc, Dimitri [> >]
Farrer, Matt J. [> >]
Krüger, Rejko mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience]
Elbaz, Alexis [> >]
Gasser, Thomas [> >]
Sharma, Manu [> >]
of, On Behalf [> >]
Genetics, The Comprehensive Unbiased Risk Factor Assessment For [> >]
consortium, Environment In Parkinson Textquoterights Disease Courage-P. D. [> >]
26-May-2022
Neurology
Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology
Yes
International
0028-3878
[en] Parkinson's disease ; Age of onset ; GWAS
[en] Background and Objectives: Considerable heterogeneity exists in the literature concerning genetic determinants of the age of onset (AAO) of Parkinson\textquoterights disease (PD), which could be attributed to lack of well-powered replication cohorts. The previous largest GWAS identified SNCA and TMEM175 loci on chromosome (Chr) 4 with a significant influence on AAO of PD, these have not been independently replicated. The present study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations.Methods: A meta-analysis was performed on PD AAO GWAS of 30 populations of predominantly European ancestry from the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson\textquoterights Disease (COURAGE-PD) consortium. This was followed up by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson disease Genomics Consortium (IPDGC).Results: The COURAGE-PD included a cohort of 8,535 patients with PD (91.9\%: Europeans, 9.1\%: East-Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD=11.6), with an under-representation of females (40.2\%). The heritability estimate for AAO in COURAGE-PD was 0.083 (SE=0.057). None of the loci reached genome-wide significance (P\<5x10-8). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published TMEM175 variant as genetic determinant of AAO of PD with Bonferroni-corrected nominal levels of significance (P\<0.025): (rs34311866:β(SE)COURAGE=0.477(0.203), PCOURAGE=0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (Ntotal=25,950) led to the identification of two genome-wide significant association signals on Chr 4, including the previously reported SNCA locus (rs983361:β(SE)COURAGE+IPDGC=0.720(0.122), PCOURAGE+IPDGC=3.13x10-9) and a novel BST1 locus (rs4698412:β(SE)COURAGE+IPDGC=-0.526(0.096), PCOURAGE+IPDGC=4.41x10-8).Discussion: Our study further refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of BST1 as a novel AAO PD locus. These findings open a new direction for the development of treatments to delay the onset of PD.
Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) ; Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group)
Fonds National de la Recherche - FnR
Researchers ; Professionals
http://hdl.handle.net/10993/51393
10.1212/WNL.0000000000200699
https://n.neurology.org/content/early/2022/05/26/WNL.0000000000200699
FnR ; FNR11264123 > Rejko Krüger > NCER-PD > Ncer-pd > 01/01/2015 > 30/11/2020 > 2015

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