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.
| Original language | English |
|---|---|
| Pages (from-to) | 787-793 |
| Number of pages | 7 |
| Journal | Nature Genetics |
| Volume | 53 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 2021 |
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In: Nature Genetics, Vol. 53, No. 6, 06.2021, p. 787-793.
Research output: Contribution to journal › Article › peer-review
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 - Funding Information: Brigham and Women’s Hospital holds a US provisional patent application on the PHS for predicting PD progression, on which C.R.S. is named as inventor. Outside this work, C.R.S. has served as consultant, scientific collaborator or on scientific advisory boards for Sanofi, Berg Health, Pfizer and Biogen, and has received grants from the NIH, US Department of Defense, American Parkinson Disease Association, and the Michael J Fox Foundation (MJFF). G.L., J.J.L., J.M., A.E., J.H.G., A.Y.H., S.K., P.T., S.S.A., J.S.P. and M.C.C. report no relevant financial or other conflicts of interest in relation to this study. M.A.S. has no conflict of interest related to this work. Outside this work, M.A.S. has received grants from NINDS, DoD, MJFF, Farmer Family Foundation, and has served as a consultant to commercial programs for Eli Lilly & Co (data monitoring committee), Prevail Therapeutics (scientific advisory board), Denali Therapeutics (scientific advisory board), nQ Medical (scientific advisory board), Chase Therapeutics (scientific advisory board) and Partner Therapeutics (scientific advisory board). A.-M.W. has received research funding from the ALS Association, the Parkinson’s Foundation, has participated in clinical trials funded by Acorda, Biogen, Bristol-Myers Squibb, Sanofi/Genzyme, Pfizer and Abbvie, and received consultant payments from Mitsubishi Tanabe and from Accordant. T.M.H. has no conflict of interest related to this work. Outside this work, he has received honoraria for consulting in advisory boards for Boston Scientific and Medtronic. J.-C.C. has no conflict of interest related to this work. Outside this work, J.C.C. has received honoraria for consulting in advisory boards for Abbvie, Actelion, Air Liquide, Biogen, BMS, BrainEver, Clevexel, Denali, Pfizer, Theranexus and Zambon. B.R. is an employee of and holds equity in Praxis Precision Medicines and is advisor for Caraway Therapeutics and Brain Neurotherapy Bio. I.S. is Principal Investigator of a MJFF Computational Science Grant (2017–19). S.K. is supported by Multiple Sclerosis of Western-Australia (MSWA) and the Perron Institute. P.H. is a Scientific Advisor of Neuron23. J.J.v.H. has no conflict of interest related to this work. Outside this work, J.J.v.H. has received grants from the Alkemade-Keuls Foundation, Stichting Parkinson Fonds, Parkinson Vereniging, the Netherlands Organisation for Health Research and Development, the Netherlands Organisation for Scientific Research, Hersenstichting, AbbVie, MJFF, and research support from Hoffmann-La-Roche, Lundbeck and the Centre of Human Drug Research. B.M. has no conflict related to this work. Outside this work, B.M. has received honoraria for consultancy from Roche, Biogen, AbbVie, Servier and Amprion. B.M. is member of the executive steering committee of the Parkinson Progression Marker Initiative and Principal Investigator of the Systemic Synuclein Sampling Study of the MJFF for Parkinson’s Research and has received research funding from the Deutsche Forschungsgemeinschaft (DFG), EU (Horizon2020), Parkinson Fonds Deutschland, Deutsche Parkinson Vereinigung, Parkinson’s Foundation and MJFF. R.A.B. has no conflict of interest related to this work. Outside this work, R.A.B. has received consultancy monies from LCT, FCDI, Novo Nordisk, Cellino, Sana, UC, has received royalties from Wiley and Springer Nature, grant funding from CPT, NIHR Cambridge Biomedical Research Centre (146281), the UK Medical Research Council (MRC), Wellcome Trust (203151/Z/16/Z) and Rosetrees Trust (A1519 M654). C.H.W.-G. has no conflict of interest related to this work. C.H.W.-G. is supported by a RCUK UKRI Research Innovation Fellowship awarded by the MRC (MR/R007446/1) and the NIHR Cambridge Biomedical Research Centre, and receives grant support from MJFF, the Evelyn Trust, the Cure Parkinson’s Trust, Parkinson’s UK, the Rosetrees Trust and the Cambridge Centre for Parkinson-Plus. C.H.W.-G. has received honoraria from Lundbeck and consultancy payments from Modus Outcomes and Evidera. C.T. is supported by EU Grant Horizon 2020/propag-ageing and the MJFF. C.K. serves as a medical advisor to Centogene for genetic testing reports in the fields of movement disorders and dementia, excluding Parkinson’s disease. Funding Information: We are grateful to O. Nemirovsky for his philanthropic support, encouragement and insights. We thank all study participants, their families and friends for their support and participation, and our study coordinators for making this work possible. We thank A. Brown at Partners HealthCare Personalized Medicine and Y. Kuras at Brigham and Women’s Hospital for technical assistance. The study was funded in part by philanthropic support (to Brigham & Women’s Hospital and C.R.S.) for Illumina MEGA chip genotyping; and in part by NINDS and NIA R01NS115144 (to C.R.S.), which funded genotyping for the PHS validation cohorts EPIPARK and HBS2. The work of C.R.S. was supported by NIH grants NINDS/NIA R01NS115144, U01NS095736, U01NS100603, and the American Parkinson Disease Association Center for Advanced Parkinson Research. T.M.H. is funded by NIH grant K23NS099380. While this manuscript was in revision, G.L. transferred to a new position at Sun Yat-sen University, where he received support from the National Natural Science Foundation of China (project no. 31900475), the Fundamental Research Funds for the Central Universities (project no. 19ykpy146), Young Talent Recruitment Project of Guangdong (project no. 2019QN01Y139) and Shenzhen Basic Research Project (project no. JCYJ20190807161601692). For each individual cohort, acknowledgements are listed in the Supplementary Note. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/6
Y1 - 2021/6
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
U2 - 10.1038/s41588-021-00847-6
DO - 10.1038/s41588-021-00847-6
M3 - Article
C2 - 33958783
AN - SCOPUS:85105378321
SN - 1061-4036
VL - 53
SP - 787
EP - 793
JO - Nature Genetics
JF - Nature Genetics
IS - 6
ER -