Genome-wide Association and Meta-analysis of Age at Onset in Parkinson Disease: Evidence From the COURAGE-PD Consortium. (16th August 2022)

• Record Type: Journal Article
• Authors: 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;
• Is Part Of: Neurology. Volume 99:Number 7(2022)
• Page Start: e698
• Page End: e710
• Publication Date: 2022-08-16
• Subjects: Neurology -- Periodicals; Neurology -- Periodicals; Neurologie -- Périodiques; 616.8
• DOI: 10.1212/WNL.0000000000200699
• Languages: English
• ISSNs: 0028-3878

Abstract

Abstract : Background and Objectives: 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 SNCA and TMEM175 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. 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'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). Results: 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 ( p < 5 × 10 −8 ). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published TMEM175 variant as a genetic determinant of the AAO of PD with Bonferroni-corrected nominal levels of significance ( p < 0.025): (rs34311866: β(SE)COURAGE = 0.477(0.203), p COURAGE = 0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (Ntotal = 25, 950) led to the identification of 2 genome-wide significant association signals on Chr 4, including the previously reported SNCA locus (rs983361: β(SE)COURAGE+IPDGC = 0.720(0.122), p COURAGE+IPDGC = 3.13 × 10 −9 ) and a novel BST1 locus (rs4698412: β(SE)COURAGE+IPDGC = −0.526(0.096), p COURAGE+IPDGC = 4.41 × 10 −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.