Repository logo
 

Genetic risk of Parkinson disease and progression:: An analysis of 13 longitudinal cohorts.

Accepted version
Peer-reviewed

Change log

Authors

Iwaki, Hirotaka 
Blauwendraat, Cornelis 
Liu, Ganqiang 
Maple-Grødem, Jodi  ORCID logo  https://orcid.org/0000-0001-7142-0078

Abstract

OBJECTIVE: To determine if any association between previously identified alleles that confer risk for Parkinson disease and variables measuring disease progression. METHODS: We 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. RESULTS: We confirmed the importance of GBA on phenotypes. GBA variants 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 of GBA variants with motor/cognitive declines. The other genotype-phenotype associations include an intergenic variant near LRRK2 and 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 in PMVK and the development of wearing-off effects (HR 1.66 [1.19-2.31] for the C allele of rs114138760). Age at onset was associated with TMEM175 variant p.M393T (-0.72 [-1.21 to -0.23] in years), the C allele of rs199347 (intronic region of GPNMB, 0.70 [0.27-1.14]), and G allele of rs1106180 (intronic region of CCDC62, 0.62 [0.21-1.03]). CONCLUSIONS: This study provides evidence that alleles associated with Parkinson disease risk, in particular GBA variants, 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.

Description

Keywords

31 Biological Sciences, 32 Biomedical and Clinical Sciences, 3105 Genetics, Neurodegenerative, Prevention, Brain Disorders, Aging, Clinical Research, Neurosciences, Parkinson's Disease, Genetics, 2 Aetiology, 2.1 Biological and endogenous factors, Neurological

Journal Title

Neurol Genet

Conference Name

Journal ISSN

2376-7839
2376-7839

Volume Title

5

Publisher

Ovid Technologies (Wolters Kluwer Health)

Rights

All rights reserved
Sponsorship
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
The Intramural Research Program the National Institute on Aging (NIA, Z01-AG000949-02), Biogen Idec, and the Michael J Fox Foundation for Parkinson’s Research