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Grover, S.* ; Ashwin, A.K.S.* ; Pihlstrom, L.* ; Domenighetti, C.* ; Schulte, C.* ; Sugier, P.E.* ; Radivojkov-Blagojevic, M. ; Lichtner, P. ; Mohamed, O.* ; Portugal, B.* ; Landoulsi, Z.* ; May, P.* ; Bobbili, D.R.* ; 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.* ; Bloem, B.R.* ; Singleton, A.B.* ; Aasly, J.O.* ; Toft, M.F.* ; 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.J.* ; Hellberg, C.* ; Clarke, C.E.* ; Morrison, K.E.* ; Krainc, D.* ; Farrer, M.J.* ; Kruger, R.* ; Elbaz, A.* ; Gasser, T.* ; Sharma, M.*

Genome-wide association and meta-analysis of age-at-onset in parkinson disease: Evidence from COURAGE-PD consortium.

Neurology 99, e698-e710 (2022)

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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), P_COURAGE=0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (N_total=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), P_{COURAGE+IPDGC}=3.13x10^-9) and a novel BST1 locus (rs4698412:β(SE)_{COURAGE+IPDGC}=-0.526(0.096), P_{COURAGE+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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Age At Onset ; Burden Of Disease ; Duration Of Disease ; Genetic Heritability ; Parkinson’s Disease

ISSN (print) / ISBN 0028-3878

e-ISSN 1526-632X

Journal Neurology

Quellenangaben Volume: 99, Issue: 7, Pages: e698-e710

Publisher Lippincott Williams & Wilkins

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Human Genetics (IHG)

Grants EU Joint Program for Neurodegenerative Disease research