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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Polygenic Resilience Modulates the Penetrance of Parkinson Disease Genetic Risk Factors
Annals of Neurology, Volume 92, No. 2, Year 2022
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Description
Objective: The aim of the current study is to understand why some individuals avoid developing Parkinson disease (PD) despite being at relatively high genetic risk, using the largest datasets of individual-level genetic data available. Methods: We calculated polygenic risk score to identify controls and matched PD cases with the highest burden of genetic risk for PD in the discovery cohort (International Parkinson's Disease Genomics Consortium, 7,204 PD cases and 9,412 controls) and validation cohorts (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease, 8,968 cases and 7,598 controls; UK Biobank, 2,639 PD cases and 14,301 controls; Accelerating Medicines Partnership–Parkinson's Disease Initiative, 2,248 cases and 2,817 controls). A genome-wide association study meta-analysis was performed on these individuals to understand genetic variation associated with resistance to disease. We further constructed a polygenic resilience score, and performed multimarker analysis of genomic annotation (MAGMA) gene-based analyses and functional enrichment analyses. Results: A higher polygenic resilience score was associated with a lower risk for PD (β = −0.054, standard error [SE] = 0.022, p = 0.013). Although no single locus reached genome-wide significance, MAGMA gene-based analyses nominated TBCA as a putative gene. Furthermore, we estimated the narrow-sense heritability associated with resilience to PD (h2 = 0.081, SE = 0.035, p = 0.0003). Subsequent functional enrichment analysis highlighted histone methylation as a potential pathway harboring resilience alleles that could mitigate the effects of PD risk loci. Interpretation: The present study represents a novel and comprehensive assessment of heritable genetic variation contributing to PD resistance. We show that a genetic resilience score can modify the penetrance of PD genetic risk factors and therefore protect individuals carrying a high-risk genetic burden from developing PD. ANN NEUROL 2022;92:270–278. © 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
Authors & Co-Authors
Blauwendraat, Cornelis
United States, Bethesda
National Institutes of Health Nih
Makarious, Mary B.
United States, Bethesda
National Institutes of Health Nih
United States, Glen Echo
Data Tecnica International
United Kingdom, London
Ucl Queen Square Institute of Neurology
Leonard, Hampton L.
United States, Glen Echo
Data Tecnica International
United Kingdom, London
Ucl Queen Square Institute of Neurology
Kim, Jonggeol Jeff
United States, Bethesda
National Institutes of Health Nih
United Kingdom, London
Queen Mary University of London
Schulte, Claudia M.S.
Germany, Tubingen
Eberhard Karls Universität Tübingen
Noyce, Alastair John
United Kingdom, London
Queen Mary University of London
Jacobs, Benjamin Meir
United Kingdom, London
Queen Mary University of London
Foote, Isabelle Francesca
United Kingdom, London
Queen Mary University of London
Sharma, Manu
Germany, Tubingen
Eberhard Karls Universität Tübingen
Kõks, Sulev V.
Unknown Affiliation
Mellick, George D.
Unknown Affiliation
Pirker, Walter
Unknown Affiliation
Zimprich, Alexander
Unknown Affiliation
Lang, Anthony E.
Unknown Affiliation
Rogaeva, Ekaterina A.
Unknown Affiliation
Taba, Pille
Unknown Affiliation
Brice, Alexis
Unknown Affiliation
Chartier-Harlin, Marie Christine
Unknown Affiliation
Corvol, Jean Christophe
Unknown Affiliation
Domenighetti, Cloe
Unknown Affiliation
Elbaz, Alexis
Unknown Affiliation
Lesage, Suzanne
Unknown Affiliation
Mutez, Eugénie
Unknown Affiliation
Sugier, Pierre Emmanuel
Unknown Affiliation
Sreelatha, Ashwin Ashok Kumar
Unknown Affiliation
Grover, Sandeep
Unknown Affiliation
Brockmann, Kathrin
Unknown Affiliation
Deutschländer, Angela B.
Unknown Affiliation
Gasser, Thomas
Germany, Tubingen
Eberhard Karls Universität Tübingen
Krüger, Jens
Unknown Affiliation
Lichtner, Peter K.
Unknown Affiliation
Radivojkov-Blagojević, Milena
Unknown Affiliation
Dardiotis, Efthymios
Unknown Affiliation
Hadjigeorgiou, Georgios M.
Unknown Affiliation
Simitsi, Athina Maria
Unknown Affiliation
Stefanis, Leonidas
Unknown Affiliation
Annesi, Grazia
Unknown Affiliation
Brighina, Laura
Unknown Affiliation
Ferrarese, Carlo
Unknown Affiliation
Petrucci, Simona
Unknown Affiliation
Pezzoli, Gianni
Unknown Affiliation
Quattrone, Andrea
Unknown Affiliation
Straniero, Letizia
Unknown Affiliation
Gagliardi, Monica
Unknown Affiliation
Valente, Enza Maria
Unknown Affiliation
Zecchinelli, A. Lena
Unknown Affiliation
Hattori, Nobutaka
Unknown Affiliation
Nakayama, Akiyoshi
Unknown Affiliation
Matsuo, Hirotaka
Unknown Affiliation
Nishioka, Kenya
Unknown Affiliation
Bobbili, Dheeraj Reddy
Unknown Affiliation
Krüger, Rejko
Unknown Affiliation
Landoulsi, Zied
Unknown Affiliation
May, Patrick
Unknown Affiliation
Pavelka, Lukas
Unknown Affiliation
Bloem, Bastiaan R.
Unknown Affiliation
van de Warrenburg, Bart P.C.
Unknown Affiliation
Aasly, Jan Olav
Unknown Affiliation
Pihlstrom, Lasse
Unknown Affiliation
Toft, Mathias
Unknown Affiliation
Ferreira, Joaquim José
Unknown Affiliation
Guedes, Leonor Correia
Unknown Affiliation
Bardien, Soraya
Unknown Affiliation
Carr, Jonathan A.
Unknown Affiliation
Chung, Sun-ju
Unknown Affiliation
Kim, Yunjoong
Unknown Affiliation
Diez-Fairen, Monica
Unknown Affiliation
Ezquerra, Mario
Unknown Affiliation
Pástor, Pau
Unknown Affiliation
Tolosa, Eduardo S.
Unknown Affiliation
Belin, Andrea Carmine
Unknown Affiliation
Pedersen, Nancy Lee
Unknown Affiliation
Puschmann, Andreas J.
Unknown Affiliation
Ran, Caroline
Unknown Affiliation
Rödström, Emil Ygland
Unknown Affiliation
Wirdefeldt, Karin
Unknown Affiliation
Clarke, Carl E.
Unknown Affiliation
Morrison, Karen E.
Unknown Affiliation
Tan, Manuela M.X.
Unknown Affiliation
Edsall, Connor
Unknown Affiliation
Farrer, Matthew J.
Unknown Affiliation
Krainc, Dimitri
Unknown Affiliation
Singleton, Andrew B.
Unknown Affiliation
Burbulla, Lena F.
Unknown Affiliation
Hernandez, Dena G.
Unknown Affiliation
Nalls, Mike A.
United States, Bethesda
National Institutes of Health Nih
United States, Glen Echo
Data Tecnica International
Singleton, Andrew B.
United States, Bethesda
National Institutes of Health Nih
Bandres-Ciga, Sara
United States, Bethesda
National Institutes of Health Nih
Statistics
Citations: 6
Authors: 88
Affiliations: 5
Identifiers
Doi:
10.1002/ana.26416
ISSN:
03645134
Research Areas
Cancer
Genetics And Genomics
Study Design
Cohort Study
Study Approach
Systematic review