Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson’s disease

G. Liu; J. Peng; Z. Liao; J.J. Locascio; J-C Corvol; F. Zhu; X. Dong; J. Maple-Grødem; M.C. Campbell; A. Elbaz; S. Lesage; A. Brice; G. Mangone; J.H. Growdon; A.Y. Hung; M.A. Schwarzschild; M.T. Hayes; A-M Wills; T.M. Herrington; B. Ravina; I. Shoulson; P. Taba; S. Kõks; T.G. Beach; F. Cormier-Dequaire; G. Alves; O-B Tysnes; J.S. Perlmutter; P. Heutink; S.S. Amr; J.J. van Hilten; M. Kasten; B. Mollenhauer; C. Trenkwalder; C. Klein; R.A. Barker; C.H. Williams-Gray; J. Marinus; C.R. Scherzer

doi:10.1038/s41588-021-00847-6

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Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson’s disease

Journal article

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Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson’s disease

G. Liu, J. Peng, Z. Liao, J.J. Locascio, J-C Corvol, F. Zhu, X. Dong, J. Maple-Grødem, M.C. Campbell, A. Elbaz, …

Nature Genetics, Vol.53, pp.787-793

2021

DOI: https://doi.org/10.1038/s41588-021-00847-6

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Abstract

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.

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Title: Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson’s disease
Authors/Creators: G. Liu (Author/Creator) - Brigham and Women's Hospital
J. Peng (Author/Creator) - Brigham and Women's Hospital
Z. Liao (Author/Creator) - Brigham and Women's Hospital
J.J. Locascio (Author/Creator) - Massachusetts General Hospital
J-C Corvol (Author/Creator) - Université Paris Cité
F. Zhu (Author/Creator) - Brigham and Women's Hospital
X. Dong (Author/Creator) - Brigham and Women's Hospital
J. Maple-Grødem (Author/Creator) - University of Stavanger
M.C. Campbell (Author/Creator) - Washington University in St. Louis
A. Elbaz (Author/Creator) - Université de Versailles Saint-Quentin-en-Yvelines
S. Lesage (Author/Creator) - Université Paris Cité
A. Brice (Author/Creator) - Université Paris Cité
G. Mangone (Author/Creator) - Université Paris Cité
J.H. Growdon (Author/Creator) - Massachusetts General Hospital
A.Y. Hung (Author/Creator) - Massachusetts General Hospital
M.A. Schwarzschild (Author/Creator) - Massachusetts General Hospital
M.T. Hayes (Author/Creator) - Brigham and Women's Hospital
A-M Wills (Author/Creator) - Massachusetts General Hospital
T.M. Herrington (Author/Creator) - Massachusetts General Hospital
B. Ravina (Author/Creator) - Precision for Medicine (United States)
I. Shoulson (Author/Creator) - University of Rochester
P. Taba (Author/Creator) - University of Tartu
S. Kõks (Author/Creator) - Murdoch University
T.G. Beach (Author/Creator) - Banner Health
F. Cormier-Dequaire (Author/Creator) - Université Paris Cité
G. Alves (Author/Creator) - University of Stavanger
O-B Tysnes (Author/Creator) - University of Bergen
J.S. Perlmutter (Author/Creator) - Washington University in St. Louis
P. Heutink (Author/Creator) - German Center for Neurodegenerative Diseases
S.S. Amr (Author/Creator) - Mass General Brigham
J.J. van Hilten (Author/Creator) - Leiden University Medical Center
M. Kasten (Author/Creator) - University of Lübeck
B. Mollenhauer (Author/Creator) - University of Göttingen
C. Trenkwalder (Author/Creator) - University of Göttingen
C. Klein (Author/Creator) - University of Lübeck
R.A. Barker (Author/Creator) - Wellcome/MRC Cambridge Stem Cell Institute
C.H. Williams-Gray (Author/Creator) - University of Cambridge
J. Marinus (Author/Creator) - Leiden University Medical Center
C.R. Scherzer (Author/Creator) - Brigham and Women's Hospital
Publication Details: Nature Genetics, Vol.53, pp.787-793
Publisher: Nature Publishing Group
Identifiers: 991005542588307891
Copyright: © 2021 Springer Nature Limited
Murdoch Affiliation: Centre for Molecular Medicine and Innovative Therapeutics
Language: English
Resource Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.52 Neurodegenerative Diseases; 1.52.67 Parkinson's Disease
Web Of Science research areas: Genetics & Heredity
ESI research areas: Molecular Biology & Genetics