PT  - JOURNAL ARTICLE
AU  - Iwaki, Hirotaka
AU  - Blauwendraat, Cornelis
AU  - Leonard, Hampton L.
AU  - Liu, Ganqiang
AU  - Maple-Grødem, Jodi
AU  - Corvol, Jean-Christophe
AU  - Pihlstrøm, Lasse
AU  - van Nimwegen, Marlies
AU  - Hutten, Samantha J.
AU  - Nguyen, Khanh-Dung H.
AU  - Rick, Jacqueline
AU  - Eberly, Shirley
AU  - Faghri, Faraz
AU  - Auinger, Peggy
AU  - Scott, Kirsten M.
AU  - Wijeyekoon, Ruwani
AU  - Van Deerlin, Vivianna M.
AU  - Hernandez, Dena G.
AU  - Day-Williams, Aaron G.
AU  - Brice, Alexis
AU  - Alves, Guido
AU  - Noyce, Alastair J.
AU  - Tysnes, Ole-Bjørn
AU  - Evans, Jonathan R.
AU  - Breen, David P.
AU  - Estrada, Karol
AU  - Wegel, Claire E.
AU  - Danjou, Fabrice
AU  - Simon, David K.
AU  - Ravina, Bernard
AU  - Toft, Mathias
AU  - Heutink, Peter
AU  - Bloem, Bastiaan R.
AU  - Weintraub, Daniel
AU  - Barker, Roger A.
AU  - Williams-Gray, Caroline H.
AU  - van de Warrenburg, Bart P.
AU  - Van Hilten, Jacobus J.
AU  - Scherzer, Clemens R.
AU  - Singleton, Andrew B.
AU  - Nalls, Mike A.
TI  - Genetic risk of Parkinson disease and progression:
AID  - 10.1212/NXG.0000000000000348
DP  - 2019 Aug 01
TA  - Neurology Genetics
PG  - e348
VI  - 5
IP  - 4
4099  - http://ng.neurology.org/content/5/4/e348.short
4100  - http://ng.neurology.org/content/5/4/e348.full
SO  - Neurol Genet2019 Aug 01; 5
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