Genome-wide Association and Meta-analysis of Age at Onset in Parkinson Disease: Evidence From the COURAGE-PD Consortium.
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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, and the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD) Consortium
Аннотация
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.