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 Mellick; Alexander 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; 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 B Singleton; Jan Aasly; Mathias Toft; Leonor Correia Guedes; Joaquim J Ferreira; Soraya Bardien; Jonathan Carr; Eduardo Tolosa; Mario Ezquerra; Pau Pastor; Monica Diez-Fairen; Karin Wirdefeldt; Nancy L Pedersen; Caroline Ran; Andrea C Belin; Andreas Puschmann; Clara Hellberg; Carl E Clarke; Karen E Morrison; Dimitri Krainc; Matt J Farrer; Rejko Kruger; Alexis Elbaz; Thomas Gasser; Manu Sharma

doi:10.1212/WNL.0000000000200699

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

Authors: 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 Mellick ; Alexander 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 ; 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 B Singleton ; Jan Aasly ; Mathias Toft ; Leonor Correia Guedes ; Joaquim J Ferreira ; Soraya Bardien ; Jonathan Carr ; Eduardo Tolosa ; Mario Ezquerra ; Pau Pastor ; Monica Diez-Fairen ; Karin Wirdefeldt ; Nancy L Pedersen ; Caroline Ran ; Andrea C Belin ; Andreas Puschmann ; Clara Hellberg ; Carl E Clarke ; Karen E Morrison ; Dimitri Krainc ; Matt J Farrer ; Rejko Kruger ; Alexis Elbaz ; Thomas Gasser ; Manu Sharma

Citation: NEUROLOGY, Vol.99(7) : E698-E710, 2022-08

Journal Title: NEUROLOGY

ISSN: 0028-3878

Issue Date: 2022-08

MeSH: Age of Onset ; Courage* ; Female ; Genetic Predisposition to Disease / genetics ; Genome-Wide Association Study ; Humans ; Parkinson Disease* / epidemiology ; Parkinson Disease* / genetics ; Polymorphism, Single Nucleotide

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), 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..