Penetrance of Parkinson's Disease in LRRK2 p.G2019S Carriers Is Modified by a Polygenic Risk Score. Issue 5 (20th January 2020)

• Record Type: Journal Article
• Authors: Iwaki, Hirotaka; Blauwendraat, Cornelis; Makarious, Mary B.; Bandrés‐Ciga, Sara; Leonard, Hampton L.; Gibbs, J. Raphael; Hernandez, Dena G.; Scholz, Sonja W.; Faghri, Faraz; Nalls, Mike A.; Singleton, Andrew B.
• Other Names: Noyce Alastair J investigator.; Kaiyrzhanov Rauan investigator.; Middlehurst Ben investigator.; Kia Demis A investigator.; Tan Manuela investigator.; Houlden Henry investigator.; Morris Huw R investigator.; Plun‐Favreau Helene investigator.; Holmans Peter investigator.; Hardy John investigator.; Trabzuni Daniah investigator.; Quinn John investigator.; Bubb Vivien investigator.; Mok Kin Y investigator.; Kinghorn Kerri J. investigator.; Wood Nicholas W investigator.; Lewis Patrick investigator.; Schreglmann Sebastian investigator.; Lovering Ruth investigator.; R'Bibo Lea investigator.; Manzoni Claudia investigator.; Rizig Mie investigator.; Ryten Mina investigator.; Guelfi Sebastian investigator.; Escott‐Price Valentina investigator.; Chelban Viorica investigator.; Foltynie Thomas investigator.; Williams Nigel investigator.; Morrison Karen E. investigator.; Clarke Carl investigator.; Brice Alexis investigator.; Danjou Fabrice investigator.; Lesage Suzanne investigator.; Corvol Jean‐Christophe investigator.; Martinez Maria investigator.; Schulte Claudia investigator.; Brockmann Kathrin investigator.; Simón‐Sánchez Javier investigator.; Heutink Peter investigator.; Rizzu Patrizia investigator.; Sharma Manu investigator.; Gasser Thomas investigator.; Cookson Mark R investigator.; Bandres‐Ciga Sara investigator.; Blauwendraat Cornelis investigator.; Craig David W. investigator.; Billingsley Kimberley investigator.; Narendra Derek investigator.; Faghri Faraz investigator.; Raphael Gibbs J investigator.; Hernandez Dena G. investigator.; Keuren‐Jensen Kendall Van investigator.; Shulman Joshua M. investigator.; Iwaki Hirotaka investigator.; Leonard Hampton L. investigator.; Nalls Mike A. investigator.; Robak Laurie investigator.; Bras Jose investigator.; Guerreiro Rita investigator.; Lubbe Steven investigator.; Finkbeiner Steven investigator.; Mencacci Niccolo E. investigator.; Lungu Codrin investigator.; Singleton Andrew B investigator.; Scholz Sonja W. investigator.; Reed Xylena investigator.; Alcalay Roy N. investigator.; Gan‐Or Ziv investigator.; Rouleau Guy A. investigator.; Krohn Lynne investigator.; van Hilten Jacobus J investigator.; Marinus Johan investigator.; Adarmes‐Gómez Astrid D. investigator.; Aguilar Miquel investigator.; Alvarez Ignacio investigator.; Alvarez Victoria investigator.; Barrero Francisco Javier investigator.; Yarza Jesús Alberto Bergareche investigator.; Bernal‐Bernal Inmaculada investigator.; Blazquez Marta investigator.; Bonilla‐Toribio Marta investigator.; Botía Juan A. investigator.; Boungiorno María Teresa investigator.; Buiza‐Rueda Dolores investigator.; Cámara Ana investigator.; Carrillo Fátima investigator.; Carrión‐Claro Mario investigator.; Cerdan Debora investigator.; Clarimón Jordi investigator.; Compta Yaroslau investigator.; Diez‐Fairen Monica investigator.; Dols‐Icardo Oriol investigator.; Duarte Jacinto investigator.; Duran Raquel investigator.; Escamilla‐Sevilla Francisco investigator.; Ezquerra Mario investigator.; Feliz Cici investigator.; 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Aitkulova Akbota investigator.; Zholdybayeva Elena investigator.; Zharmukhanov Zharkyn investigator.; Kaishybayeva Gulnaz investigator.; Karimova Altynay investigator.; Sadykova Dinara investigator.;
• Is Part Of: Movement disorders. Volume 35:Issue 5(2020)
• Page Start: 774
• Page End: 780
• Publication Date: 2020-01-20
• Subjects: G2019S -- genetics -- LRRK2 -- Parkinson's disease -- polygenic risk score; Movement disorders -- Periodicals; 610
• DOI: 10.1002/mds.27974
• Languages: English
• ISSNs: 0885-3185

Abstract

Abstract: Background: Although the leucine‐rich repeat kinase 2 p.G2019S mutation has been demonstrated to be a strong risk factor for PD, factors that contribute to penetrance among carriers, other than aging, have not been well identified. Objectives: To evaluate whether a cumulative genetic risk identified in the recent genome‐wide study is associated with penetrance of PD among p.G2019S mutation carriers. Methods: We included p.G2019S heterozygote carriers with European ancestry in three genetic cohorts in which the mutation carriers with and without PD were selectively recruited. We also included the carriers from two data sets: one from a case‐control setting without selection of mutation carriers and the other from a population sampling. Associations between polygenic risk score constructed from 89 variants reported recently and PD were tested and meta‐analyzed. We also explored the interaction of age and PRS. Results: After excluding eight homozygotes, 833 p.G2019S heterozygote carriers (439 PD and 394 unaffected) were analyzed. Polygenic risk score was associated with a higher penetrance of PD (odds ratio: 1.34; 95% confidence interval: [1.09, 1.64] per +1 standard deviation; P = 0.005). In addition, associations with polygenic risk score and penetrance were stronger in the younger participants (main effect: odds ratio 1.28 [1.04, 1.58] per +1 standard deviation; P = 0.022; interaction effect: odds ratio 0.78 [0.64, 0.94] per +1 standard deviation and + 10 years of age; P = 0.008). Conclusions: Our results suggest that there is a genetic contribution for penetrance of PD among p.G2019S carriers. These results have important etiological consequences and potential impact on the selection of subjects for clinical trials. © 2020 International Parkinson and Movement Disorder Society