Background and objectives: Considerable heterogeneity exists in the literature concerning genetic determinants of the age of onset (AAO) of Parkinson's disease (PD), which could be attributed to lack of well-powered replication cohorts. The previous largest GWAS identified SNCA and TMEM175 loci on chromosome (Chr) 4 with a significant influence on AAO of PD, these have not been independently replicated. The present 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 up 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 included a cohort of 8,535 patients with PD (91.9%: Europeans, 9.1%: East-Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD=11.6), with an under-representation 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<5x10-8). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published TMEM175 variant as genetic determinant of AAO of PD with Bonferroni-corrected nominal levels of significance (P<0.025): (rs34311866:β(SE)COURAGE=0.477(0.203), PCOURAGE=0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (Ntotal=25,950) led to the identification of two genome-wide significant association signals on Chr 4, including the previously reported SNCA locus (rs983361:β(SE)COURAGE+IPDGC=0.720(0.122), PCOURAGE+IPDGC=3.13x10-9) and a novel BST1 locus (rs4698412:β(SE)COURAGE+IPDGC=-0.526(0.096), PCOURAGE+IPDGC=4.41x10-8). 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.
Genome-wide Association and Meta-analysis of Age-at-Onset in Parkinson Disease. Evidence From COURAGE-PD Consortium / Grover, Sandeep; Ashwin, Ashok Kumar Sreelatha; 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 Pc; 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. - In: NEUROLOGY. - ISSN 0028-3878. - (2022). [10.1212/WNL.0000000000200699]
Genome-wide Association and Meta-analysis of Age-at-Onset in Parkinson Disease. Evidence From COURAGE-PD Consortium
Valente, Enza Maria;Petrucci, Simona;
2022
Abstract
Background and objectives: Considerable heterogeneity exists in the literature concerning genetic determinants of the age of onset (AAO) of Parkinson's disease (PD), which could be attributed to lack of well-powered replication cohorts. The previous largest GWAS identified SNCA and TMEM175 loci on chromosome (Chr) 4 with a significant influence on AAO of PD, these have not been independently replicated. The present 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 up 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 included a cohort of 8,535 patients with PD (91.9%: Europeans, 9.1%: East-Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD=11.6), with an under-representation 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<5x10-8). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published TMEM175 variant as genetic determinant of AAO of PD with Bonferroni-corrected nominal levels of significance (P<0.025): (rs34311866:β(SE)COURAGE=0.477(0.203), PCOURAGE=0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (Ntotal=25,950) led to the identification of two genome-wide significant association signals on Chr 4, including the previously reported SNCA locus (rs983361:β(SE)COURAGE+IPDGC=0.720(0.122), PCOURAGE+IPDGC=3.13x10-9) and a novel BST1 locus (rs4698412:β(SE)COURAGE+IPDGC=-0.526(0.096), PCOURAGE+IPDGC=4.41x10-8). 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.File | Dimensione | Formato | |
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