TY - JOUR
T1 - Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson’s disease
AU - International Genetics of Parkinson Disease Progression (IGPP) Consortium
AU - Liu, Ganqiang
AU - Peng, Jiajie
AU - Liao, Zhixiang
AU - Locascio, Joseph J.
AU - Corvol, Jean Christophe
AU - Zhu, Frank
AU - Dong, Xianjun
AU - Maple-Grødem, Jodi
AU - Campbell, Meghan C.
AU - Elbaz, Alexis
AU - Lesage, Suzanne
AU - Brice, Alexis
AU - Mangone, Graziella
AU - Growdon, John H.
AU - Hung, Albert Y.
AU - Schwarzschild, Michael A.
AU - Hayes, Michael T.
AU - Wills, Anne Marie
AU - Herrington, Todd M.
AU - Ravina, Bernard
AU - Shoulson, Ira
AU - Taba, Pille
AU - Kõks, Sulev
AU - Beach, Thomas G.
AU - Cormier-Dequaire, Florence
AU - Alves, Guido
AU - Tysnes, Ole Bjørn
AU - Perlmutter, Joel S.
AU - Heutink, Peter
AU - Amr, Sami S.
AU - van Hilten, Jacobus J.
AU - Kasten, Meike
AU - Mollenhauer, Brit
AU - Trenkwalder, Claudia
AU - Klein, Christine
AU - Barker, Roger A.
AU - Williams-Gray, Caroline H.
AU - Marinus, Johan
AU - van Hilten, Jacobus J.
AU - Scherzer, Clemens R.
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021
Y1 - 2021
N2 - A key driver of patients’ well-being and clinical trials for Parkinson’s disease (PD) is the course that the disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia, a major determinant for quality of life, we performed a longitudinal genome-wide survival study of 11.2 million variants in 3,821 patients with PD over 31,053 visits. We discover RIMS2 as a progression locus and confirm this in a replicate population (hazard ratio (HR) = 4.77, P = 2.78 × 10−11), identify suggestive evidence for TMEM108 (HR = 2.86, P = 2.09 × 10−8) and WWOX (HR = 2.12, P = 2.37 × 10−8) as progression loci, and confirm associations for GBA (HR = 1.93, P = 0.0002) and APOE (HR = 1.48, P = 0.001). Polygenic progression scores exhibit a substantial aggregate association with dementia risk, while polygenic susceptibility scores are not predictive. This study identifies a novel synaptic locus and polygenic score for cognitive disease progression in PD and proposes diverging genetic architectures of progression and susceptibility.
AB - A key driver of patients’ well-being and clinical trials for Parkinson’s disease (PD) is the course that the disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia, a major determinant for quality of life, we performed a longitudinal genome-wide survival study of 11.2 million variants in 3,821 patients with PD over 31,053 visits. We discover RIMS2 as a progression locus and confirm this in a replicate population (hazard ratio (HR) = 4.77, P = 2.78 × 10−11), identify suggestive evidence for TMEM108 (HR = 2.86, P = 2.09 × 10−8) and WWOX (HR = 2.12, P = 2.37 × 10−8) as progression loci, and confirm associations for GBA (HR = 1.93, P = 0.0002) and APOE (HR = 1.48, P = 0.001). Polygenic progression scores exhibit a substantial aggregate association with dementia risk, while polygenic susceptibility scores are not predictive. This study identifies a novel synaptic locus and polygenic score for cognitive disease progression in PD and proposes diverging genetic architectures of progression and susceptibility.
UR - http://www.scopus.com/inward/record.url?scp=85105378321&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/f204f1cd-f1b1-3d4f-9720-eb8aeb52c83a/
U2 - 10.1038/s41588-021-00847-6
DO - 10.1038/s41588-021-00847-6
M3 - Journal articles
AN - SCOPUS:85105378321
SN - 1061-4036
JO - Nature Genetics
JF - Nature Genetics
ER -
