Details

Autor(en) / Beteiligte

• Grover, Sandeep
• Kumar Sreelatha, Ashwin Ashok
• Pihlstrom, Lasse
• Domenighetti, Cloé
• Schulte, Claudia
• Sugier, Pierre-Emmanuel
• Radivojkov-Blagojevic, Milena
• Lichtner, Peter
• Mohamed, Océane
• Portugal, Berta
• Landoulsi, Zied
• May, Patrick
• Bobbili, Dheeraj
• 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
• 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
• Kruger, Rejko
• Elbaz, Alexis
• Gasser, Thomas
• Sharma, Manu

Titel

Genome-wide Association and Meta-analysis of Age at Onset in Parkinson Disease: Evidence From the COURAGE-PD Consortium

Ist Teil von

• Neurology, 2022-08, Vol.99 (7), p.e698

Ort / Verlag

United States

Erscheinungsjahr

2022

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Considerable heterogeneity exists in the literature concerning genetic determinants of the age at onset (AAO) of Parkinson disease (PD), which could be attributed to a lack of well-powered replication cohorts. The previous largest genome-wide association studies (GWAS) identified and loci on chromosome (Chr) 4 with a significant influence on the AAO of PD; these have not been independently replicated. This study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations. 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's Disease (COURAGE-PD) Consortium. This was followed by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson Disease Genomics Consortium (IPDGC). The COURAGE-PD Consortium included a cohort of 8,535 patients with PD (91.9%: Europeans and 9.1%: East Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD = 11.6), with an underrepresentation 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 ( < 5 × 10 ). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published variant as a genetic determinant of the AAO of PD with Bonferroni-corrected nominal levels of significance ( < 0.025): (rs34311866: β(SE) = 0.477(0.203), = 0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (N = 25,950) led to the identification of 2 genome-wide significant association signals on Chr 4, including the previously reported locus (rs983361: β(SE) = 0.720(0.122), = 3.13 × 10 ) and a novel locus (rs4698412: β(SE) = -0.526(0.096), = 4.41 × 10 ). Our study further refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of as a novel AAO PD locus. These findings open a new direction for the development of treatments to delay the onset of PD.