RT Journal Article
SR Electronic
T1 Genetic risk of Parkinson disease and progression:
JF Neurology Genetics
JO Neurol Genet
FD Lippincott Williams & Wilkins
SP e348
DO 10.1212/NXG.0000000000000348
VO 5
IS 4
A1 Iwaki, Hirotaka
A1 Blauwendraat, Cornelis
A1 Leonard, Hampton L.
A1 Liu, Ganqiang
A1 Maple-Grødem, Jodi
A1 Corvol, Jean-Christophe
A1 Pihlstrøm, Lasse
A1 van Nimwegen, Marlies
A1 Hutten, Samantha J.
A1 Nguyen, Khanh-Dung H.
A1 Rick, Jacqueline
A1 Eberly, Shirley
A1 Faghri, Faraz
A1 Auinger, Peggy
A1 Scott, Kirsten M.
A1 Wijeyekoon, Ruwani
A1 Van Deerlin, Vivianna M.
A1 Hernandez, Dena G.
A1 Day-Williams, Aaron G.
A1 Brice, Alexis
A1 Alves, Guido
A1 Noyce, Alastair J.
A1 Tysnes, Ole-Bjørn
A1 Evans, Jonathan R.
A1 Breen, David P.
A1 Estrada, Karol
A1 Wegel, Claire E.
A1 Danjou, Fabrice
A1 Simon, David K.
A1 Ravina, Bernard
A1 Toft, Mathias
A1 Heutink, Peter
A1 Bloem, Bastiaan R.
A1 Weintraub, Daniel
A1 Barker, Roger A.
A1 Williams-Gray, Caroline H.
A1 van de Warrenburg, Bart P.
A1 Van Hilten, Jacobus J.
A1 Scherzer, Clemens R.
A1 Singleton, Andrew B.
A1 Nalls, Mike A.
YR 2019
UL http://ng.neurology.org/content/5/4/e348.abstract
AB 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.ESS=Epworth Sleepiness Scale; FDR=false discovery rate; GRS=genetic risk score; GWAS=genome-wide association study; HR=hazard ratio; HY=Hoehn and Yahr scale; MAF=minor allele frequency; MDS=Movement Disorder Society; MMSE=Mini-Mental State Examination; MoCA=Montreal Cognitive Assessment; MSQ=Mayo Sleep Questionnaire; NMS=nonmotor symptom; OR=odds ratio; PC=principal component; PDSS=Parkinson's Disease Sleep Scale; PPMI=Parkinson's Progression Markers Initiative; RBD=rapid eye movement sleep behavior disorder; RBDSQ=RBD Screening Questionnaire; RLS=restless legs syndrome; SEADL=Schwab and England Activities of Daily Living Scale; UPDRS=Unified Parkinson's Disease Rating Scale