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

Grover, Sandeep; Kumar Sreelatha, Ashwin Ashok; Pihlstrom, Lasse; Domenighetti, Cloe; Schulte, Claudia; Sugier, Pierre-Emmanuel; Radivojkov-Blagojevic, Milena; Lichtner, Peter; Mohamed, Oceane; Portugal, Berta; Landoulsi, Zied; May, Patrick; Bobbili, Dheeraj; Edsall, Connor; Bartusch, Felix; Hanussek, Maximilian; Krueger, 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; Deutschlaender, 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; Warrenburg, Bart P. C. van de; 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; Elbaz, Alexis; Gasser, Thomas und Sharma, Manu (2022): Genome-wide Association and Meta-analysis of Age at Onset in Parkinson Disease Evidence From the COURAGE-PD Consortium. In: Neurology, Bd. 99, Nr. 7, E698-E710

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 x 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: beta(SE)(COURAGE) = 0.477(0.203), p(COURAGE) = 0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (N-total = 25,950) led to the identification of 2 genome-wide significant association signals on Chr 4, including the previously reported SNCA locus (rs983361: beta(SE)(COURAGE+IPDGC) = 0.720(0.122), p(COURAGE+IPDGC) = 3.13 x 10(-9)) and a novel BST1 locus (rs4698412: beta(SE)(COURAGE+IPDGC) = -0.526(0.096), p(COURAGE+IPDGC) = 4.41 x 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin ; Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0028-3878
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198