PT  - JOURNAL ARTICLE
AU  - Hirotaka Iwaki
AU  - Cornelis Blauwendraat
AU  - Hampton L. Leonard
AU  - Jonggeol J. Kim
AU  - Ganqiang Liu
AU  - Jodi Maple-Grødem
AU  - Jean-Christophe Corvol
AU  - Lasse Pihlstrøm
AU  - Marlies van Nimwegen
AU  - Samantha J. Hutten
AU  - H. Nguyen Khanh-Dung
AU  - Jacqueline Rick
AU  - Shirley Eberly
AU  - Faraz Faghri
AU  - Peggy Auinger
AU  - Kirsten M. Scott
AU  - Ruwani Wijeyekoon
AU  - Vivianna M. Van Deerlin
AU  - Dena G. Hernandez
AU  - J. Raphael Gibbs
AU  - Kumaraswamy Naidu Chitrala
AU  - Aaron G. Day-Williams
AU  - Alexis Brice
AU  - Guido Alves
AU  - Alastair J. Noyce
AU  - Ole-Bjørn Tysnes
AU  - Jonathan R. Evans
AU  - David P. Breen
AU  - Karol Estrada
AU  - Claire E. Wegel
AU  - Fabrice Danjou
AU  - David K. Simon
AU  - Ole Andreassen
AU  - Bernard Ravina
AU  - Mathias Toft
AU  - Peter Heutink
AU  - Bastiaan R. Bloem
AU  - Daniel Weintraub
AU  - Roger A. Barker
AU  - Caroline H. Williams-Gray
AU  - Bart P. van de Warrenburg
AU  - Jacobus J. Van Hilten
AU  - Clemens R. Scherzer
AU  - Andrew B. Singleton
AU  - Mike A. Nalls
TI  - Genome-wide association study of Parkinson’s disease progression biomarkers in 12 longitudinal patients’ cohorts
AID  - 10.1101/585836
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 585836
4099  - http://biorxiv.org/content/early/2019/03/27/585836.short
4100  - http://biorxiv.org/content/early/2019/03/27/585836.full
AB  - Background Several reports have identified different patterns of Parkinson’s disease progression in individuals carrying missense variants in the GBA or LRRK2 genes. The overall contribution of genetic factors to the severity and progression of Parkinson’s disease, however, has not been well studied.Objectives To test the association between genetic variants and the clinical features and progression of Parkinson’s disease on a genome-wide scale.Methods We accumulated individual data from 12 longitudinal cohorts in a total of 4,093 patients with 25,254 observations over a median of 3.81 years. Genome-wide associations were evaluated for 25 cross-sectional and longitudinal phenotypes. Specific variants of interest, including 90 recently-identified disease risk variants, were also investigated for the associations with these phenotypes.Results Two variants were genome-wide significant. Rs382940(T>A), within the intron of SLC44A1, was associated with reaching Hoehn and Yahr stage 3 or higher faster (HR 2.04 [1.58, 2.62], P-value = 3.46E-8). Rs61863020(G>A), an intergenic variant and eQTL for ADRA2A, was associated with a lower prevalence of insomnia at baseline (OR 0.63 [0,52, 0.75], P-value = 4.74E-8). In the targeted analysis, we found nine associations between known Parkinson’s risk variants and more severe motor/cognitive symptoms. Also, we replicated previous reports of GBA coding variants (rs2230288: p.E365K, rs75548401: p.T408M) being associated with greater motor and cognitive decline over time, and APOE E4 tagging variant (rs429358) being associated with greater cognitive deficits in patients.Conclusions We identified novel genetic factors associated with heterogeneity of progression in Parkinson’s disease. The results provide new insights into the pathogenesis of Parkinson’s disease as well as patient stratification for clinical trials.