1. Genetic risk of Parkinson disease and progression:: An analysis of 13 longitudinal cohorts
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Peggy Auinger, David Simon, Ganqiang Liu, Daniel Weintraub, Alexis Brice, Bart P.C. van de Warrenburg, Jacqueline Rick, Bernard Ravina, Kirsten M. Scott, Hampton L. Leonard, Fabrice Danjou, Caroline H. Williams-Gray, Faraz Faghri, Hirotaka Iwaki, Ole-Bjørn Tysnes, Cornelis Blauwendraat, Lasse Pihlstrøm, Clemens R. Scherzer, Marlies van Nimwegen, Jacobus J. van Hilten, Alastair J. Noyce, Samantha J. Hutten, Mike A. Nalls, Vivianna M. van Deerlin, Peter Heutink, Roger A. Barker, Karol Estrada, Jonathan R. Evans, Aaron G. Day-Williams, Shirley Eberly, Andrew B. Singleton, Jean-Christophe Corvol, David P. Breen, Dena G. Hernandez, Khanh-Dung H. Nguyen, Bastiaan R. Bloem, Claire E. Wegel, Jodi Maple-Grødem, Mathias Toft, Guido Alves, Ruwani Wijeyekoon, Leonard, Hampton L [0000-0003-2390-8110], Maple-Grødem, Jodi [0000-0001-7142-0078], Pihlstrøm, Lasse [0000-0002-7635-8645], Faghri, Faraz [0000-0001-5744-8728], Alves, Guido [0000-0003-0630-2870], Danjou, Fabrice [0000-0002-4976-2327], and Apollo - University of Cambridge Repository
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0301 basic medicine ,Oncology ,Aging ,medicine.medical_specialty ,32 Biomedical and Clinical Sciences ,Disease ,Neurodegenerative ,3105 Genetics ,Article ,03 medical and health sciences ,0302 clinical medicine ,All institutes and research themes of the Radboud University Medical Center ,Clinical Research ,Internal medicine ,Genetics ,medicine ,2.1 Biological and endogenous factors ,ddc:610 ,Genetic variability ,Parkinson ,Allele ,Genetics (clinical) ,2 Aetiology ,Parkinson's Disease ,business.industry ,Prevention ,Hazard ratio ,Neurosciences ,Odds ratio ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,LRRK2 ,Brain Disorders ,3. Good health ,nevrologi ,030104 developmental biology ,Medical disciplines: 700::Clinical medical disciplines: 750::Neurology: 752 [VDP] ,Neurological ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,31 Biological Sciences ,Cohort study - Abstract
ObjectiveTo determine if any association between previously identified alleles that confer risk for Parkinson disease and variables measuring disease progression.MethodsWe evaluated the association between 31 risk variants and variables measuring disease progression. A total of 23,423 visits by 4,307 patients of European ancestry from 13 longitudinal cohorts in Europe, North America, and Australia were analyzed.ResultsWe confirmed the importance ofGBAon phenotypes.GBAvariants were associated with the development of daytime sleepiness (p.N370S: hazard ratio [HR] 3.28 [1.69–6.34]) and possible REM sleep behavior (p.T408M: odds ratio 6.48 [2.04–20.60]). We also replicated previously reported associations ofGBAvariants with motor/cognitive declines. The other genotype-phenotype associations include an intergenic variant nearLRRK2and the faster development of motor symptom (Hoehn and Yahr scale 3.0 HR 1.33 [1.16–1.52] for the C allele of rs76904798) and an intronic variant inPMVKand the development of wearing-off effects (HR 1.66 [1.19–2.31] for the C allele of rs114138760). Age at onset was associated withTMEM175variant p.M393T (−0.72 [−1.21 to −0.23] in years), the C allele of rs199347 (intronic region ofGPNMB, 0.70 [0.27–1.14]), and G allele of rs1106180 (intronic region ofCCDC62, 0.62 [0.21–1.03]).ConclusionsThis study provides evidence that alleles associated with Parkinson disease risk, in particularGBAvariants, also contribute to the heterogeneity of multiple motor and nonmotor aspects. Accounting for genetic variability will be a useful factor in understanding disease course and in minimizing heterogeneity in clinical trials.
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- 2018
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