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Genome-wide association and Meta-analysis of age at onset in Parkinson Disease

Grover, S., Kumar Sreelatha, A.A., Pihlstrom, L., Domenighetti, C., Schulte, C., Sugier, P-E, Radivojkov-Blagojevic, M., Lichtner, P., Mohamed, O., Portugal, B., Landoulsi, Z., May, P., Bobbili, D., Edsall, C., Bartusch, F., Hanussek, M., Krüger, J., Hernandez, D.G., Blauwendraat, C., Mellick, G.D., Zimprich, A., Pirker, W., Tan, M., Rogaeva, E., Lang, A., Kõks, S., Taba, P., Lesage, S., Brice, A., Corvol, J-C, Chartier-Harlin, M-C, Mutez, E., Brockmann, K., Deutschländer, A.B., Hadjigeorgiou, G.M., Dardiotis, E., Stefanis, L., Simitsi, A.M., Valente, E.M., Petrucci, S., Straniero, L., Zecchinelli, A., Pezzoli, G., Brighina, L., Ferrarese, C., Annesi, G., Quattrone, A., Gagliardi, M., Burbulla, L.F., Matsuo, H., Kawamura, Y., Hattori, N., Nishioka, K., Chung, S.J., Kim, Y.J., Pavelka, L., van de Warrenburg, B.P.C., Bloem, B.R., Singleton, A.B., Aasly, J., Toft, M., Guedes, L.C., Ferreira, J.J., Bardien, S., Carr, J., Tolosa, E., Ezquerra, M., Pastor, P., Diez-Fairen, M., Wirdefeldt, K., Pedersen, N.L., Ran, C., Belin, A.C., Puschmann, A., Hellberg, C., Clarke, C.E., Morrison, K.E., Krainc, D., Farrer, M.J., Krüger, R., Elbaz, A., Gasser, T. and Sharma, M. (2022) Genome-wide association and Meta-analysis of age at onset in Parkinson Disease. Neurology, 99 (7). e698-e710.

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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.

Item Type: Journal Article
Murdoch Affiliation(s): Centre for Molecular Medicine and Innovative Therapeutics
Publisher: Lippincott Williams & Wilkins
Copyright: © 2022 The Authors.
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