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

Sandeep Grover, Ashwin Ashok Kumar Sreelatha, Lasse Pihlstrom, Cloé Domenighetti, Claudia Schulte, Pierre Emmanuel Sugier, Milena Radivojkov-Blagojevic, Peter Lichtner, Océane Mohamed, Berta Portugal, Zied Landoulsi, Patrick May, Dheeraj Bobbili, Connor Edsall, Felix Bartusch, Maximilian Hanussek, Jens Krüger, Dena G. Hernandez, Cornelis Blauwendraat, George D. MellickAlexander Zimprich, Walter Pirker, Manuela Tan, Ekaterina Rogaeva, Anthony Lang, Sulev Koks, Pille Taba, Suzanne Lesage, Alexis Brice, Jean Christophe Corvol, Marie Christine Chartier-Harlin, Eugenie Mutez, Kathrin Brockmann, Angela B. Deutschländer, Georges M. 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, Rejko Kruger, Alexis Elbaz, Thomas Gasser, Manu Sharma*, and the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (Courage-PD) Consortium

*Corresponding author for this work

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3 Citations (Scopus)

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), pCOURAGE = 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), pCOURAGE+IPDGC = 3.13 × 10-9) and a novel BST1 locus (rs4698412: β(SE)COURAGE+IPDGC = -0.526(0.096), pCOURAGE+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.

Original languageEnglish
Pages (from-to)e698-e710
JournalNeurology
Volume99
Issue number7
Early online date26 May 2022
DOIs
Publication statusPublished - 16 Aug 2022
Externally publishedYes

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