Genome-wide Association and Meta-analysis of Age at Onset in Parkinson Disease
Sandeep Grover, Ashwin Ashok Kumar Sreelatha, Lasse Pihlstrøm, Cloé Domenighetti, Claudia Schulte, Pierre‐Emmanuel Sugier, Milena Radivojkov‐Blagojevic, Peter Lichtner, Océane Mohamed, Berta Portugal, Zied Landoulsi, Patrick May, Dheeraj Reddy Bobbili, Connor Edsall, Felix Bartusch, Maximilian Hanussek, Jens Krüger, Dena G. Hernandez, Cornelis Blauwendraat, George D. Mellick, Alexander Zimprich, Walter Pirker, Manuela Tan, Ekaterina Rogaeva, Anthony E. Lang, Sulev Kõks, Pille Taba, Suzanne Lesage, Alexis Brice, Jean‐Christophe Corvol, Marie‐Christine Chartier‐Harlin, Eugénie Mutez, Kathrin Brockmann, Angela Deutschländer, G. Hadjigeorgiou, Efthimos Dardiotis, Leonidas Stefanis, Athina Maria Simitsi, Enza Maria Valente, Simona Petrucci, Letizia Straniero, Anna Zecchinelli, Gianni Pezzoli, Laura Brighina, Carlo Ferrarese, Grazia Annesi, Andrea Quattrone, Monica Gagliardi, Lena F. Burbulla, Hirotaka Matsuo, Yusuke Kawamura, Nobutaka Hattori, Kenya Nishioka, Sun Ju Chung, Yun Joong Kim, Lukas Pavelka, Bart P.C. van de Warrenburg, Bastiaan R. Bloem, Andrew Singleton, Jan Aasly, Mathias Toft, Leonor Correia Guedes, Joaquim J. Ferreira, Soraya Bardien, Jonathan Carr, Eduardo Tolosa, Mario Ezquerra, Pau Pástor, Mónica Díez-Fairén, Karin Wirdefeldt, Nancy L. Pedersen, Caroline Ran, Andrea Carmine Belin, Andreas Puschmann, Clara Hellberg, Carl E Clarke, Karen Morrison, Dimitri Krainc, Matthew J. Farrer, Rejko Krüger, Alexis Elbaz, Thomas Gasser, Manu Sharma
Abstract
<h3>Background and Objectives</h3> 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 <i>SNCA</i> and <i>TMEM175</i> 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. <h3>Methods</h3> 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 Parkinson9s 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). <h3>Results</h3> 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 (<i>p</i> < 5 × 10<sup>−8</sup>). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published <i>TMEM175</i> variant as a genetic determinant of the AAO of PD with Bonferroni-corrected nominal levels of significance (<i>p</i> < 0.025): (rs34311866: β(SE)<sub>COURAGE</sub> = 0.477(0.203), <i>p</i><sub>COURAGE</sub> = 0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (N<sub>total</sub> = 25,950) led to the identification of 2 genome-wide significant association signals on Chr 4, including the previously reported <i>SNCA</i> locus (rs983361: β(SE)<sub>COURAGE+IPDGC</sub> = 0.720(0.122), <i>p</i><sub>COURAGE+IPDGC</sub> = 3.13 × 10<sup>−9</sup>) and a novel <i>BST1</i> locus (rs4698412: β(SE)<sub>COURAGE+IPDGC</sub> = −0.526(0.096), <i>p</i><sub>COURAGE+IPDGC</sub> = 4.41 × 10<sup>−8</sup>). <h3>Discussion</h3> Our study further refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of <i>BST1</i> as a novel AAO PD locus. These findings open a new direction for the development of treatments to delay the onset of PD.