TY - JOUR
T1 - Polygenic Resilience Modulates the Penetrance of Parkinson Disease Genetic Risk Factors
AU - Liu, Hui
AU - Dehestani, Mohammad
AU - Blauwendraat, Cornelis
AU - Makarious, Mary B.
AU - Leonard, Hampton
AU - Kim, Jonggeol J.
AU - Schulte, Claudia
AU - Noyce, Alastair
AU - Jacobs, Benjamin M.
AU - Foote, Isabelle
AU - Sharma, Manu
AU - Koks, Sulev
AU - Mellick, George D.
AU - Pirker, Walter
AU - Zimprich, Alexander
AU - Lang, Anthony E.
AU - Rogaeva, Ekaterina
AU - Taba, Pille
AU - Brice, Alexis
AU - Chartier-Harlin, Marie Christine
AU - Corvol, Jean Christophe
AU - Domenighetti, Cloé
AU - Elbaz, Alexis
AU - Lesage, Suzanne
AU - Mutez, Eugenie
AU - Sugier, Pierre Emmanuel
AU - Sreelatha, Ashwin Ashok Kumar
AU - Grover, Sandeep
AU - Brockmann, Kathrin
AU - Deutschländer, Angela B.
AU - Gasser, Thomas
AU - Krüger, Jens
AU - Lichtner, Peter
AU - Radivojkov-Blagojevic, Milena
AU - Schulte, Claudia
AU - Sharma, Manu
AU - Dardiotis, Efthimos
AU - Hadjigeorgiou, Georges M.
AU - Simitsi, Athina Maria
AU - Stefanis, Leonidas
AU - Annesi, Grazia
AU - Brighina, Laura
AU - Ferrarese, Carlo
AU - Petrucci, Simona
AU - Pezzoli, Gianni
AU - Quattrone, Andrea
AU - Straniero, Letizia
AU - Gagliardi, Monica
AU - Valente, Enza Maria
AU - Kruger, Rejko
AU - International Parkinson's Disease Genomics Consortium; Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease Consortium
N1 - Funding Information:
This research was supported by the NIH Intramural Research Program (National Institute on Aging, National Institute of Neurological Disorders and Stroke; project numbers 1ZIA‐NS003154, Z01‐AG000949‐02, and Z01‐ES10198).
Publisher Copyright:
© 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.
PY - 2022/8
Y1 - 2022/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85133773237&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/35599344
U2 - 10.1002/ana.26416
DO - 10.1002/ana.26416
M3 - Article
C2 - 35599344
AN - SCOPUS:85133773237
SN - 0364-5134
VL - 92
SP - 270
EP - 278
JO - Annals of Neurology
JF - Annals of Neurology
IS - 2
ER -