Genomewide association study of Parkinson's disease clinical biomarkers in 12 longitudinal patients' cohorts

Abstract

Background: Several reports have identified different patterns of Parkinson's disease progression in individuals carrying missense variants in 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 of Parkinson's disease on a genomewide scale.

Methods: We accumulated individual data from 12 longitudinal cohorts in a total of 4093 patients with 22,307 observations for a median of 3.81 years. Genomewide associations were evaluated for 25 cross-sectional and longitudinal phenotypes. Specific variants of interest, including 90 recently identified disease-risk variants, were also investigated post hoc for candidate associations with these phenotypes.

Results: Two variants were genomewide significant. Rs382940(T>A), within the intron of SLC44A1, was associated with reaching Hoehn and Yahr stage 3 or higher faster (hazard ratio 2.04 [1.58-2.62]; P value = 3.46E-8). Rs61863020(G>A), an intergenic variant and expression quantitative trait loci for α-2A adrenergic receptor, was associated with a lower prevalence of insomnia at baseline (odds ratio 0.63 [0.52-0.75]; P value = 4.74E-8). In the targeted analysis, we found 9 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 an APOE E4 tagging variant (rs429358) being associated with greater cognitive deficits in patients.

Conclusions: We identified novel genetic factors associated with heterogeneity of Parkinson's disease. The results can be used for validation or hypothesis tests regarding Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society.

Keywords: Apolipoprotein E; GBA; Parkinson's disease; genomewide association study.

FIG. 1.

Graphical overview of the analysis strategy. *Drug Interaction with Genes in Parkinson’s Disease cohort was analyzed separately depending on the genotyping system. AAD, age at diagnosis; HR, hazard ratio; HWE, Hardy-Weinberg equilibrium test; HY, Hoehn and Yahr scale; HY3, Hoehn and Yahr score; MAF, minor allele frequency; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment; OR, odds ratio; PC, principal components; PD, Parkinson’s disease; REM, rapid eye movement; Rsq, R square; SEADL, Schwab and England Activities of Daily Living Scale; UPDRS, Unified Parkinson’s Disease Rating Scale; YfD, years from diagnosis to observation. [Color figure can be viewed at wileyonlinelibrary.com]

FIG. 2.

LocusZoom plots and forest plots of the 2 genome-wide significant hits. (A) The locus plot for rs382940, which is associated with HY3. (B) The locus plot for rs61863020, which is associated with insomnia. (C) The forest plot for rs382940. (D) The forest plot for rs61863020. ADRA2A, α−2A adrenergic receptor; C.I., confidence interval; DATATOP, Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism; FE, Fixed effect mode; HBS, Harvard Biomarkers Study; HR, hazard ratio; HY3, Hoehn and Yahr score; OR, odds ratio; PARKWEST, Norwegian ParkWest Study; PDBP, Parkinson’s Disease Biomarker Program; PICNICS, Parkinsonism Incidence and Cognitive and Non-motor heterogeneity In Cambridgeshire; PPMI, Parkinson’s Progression Markers Initiative; PreCEPT, Parkinson Research Examination of CEP-1347 Trial study; PROPARK, Profiling Parkinson’s Disease Study; Rsq, R square RE, Random effect model.

FIG. 3.

Heatmap of the Parkinson’s disease genome-wide association study (GWAS) loci associated with progression markers. Cream, P value >0.05; light green, P value <0.05; green, P value <0.002; blue, P value <5.68E-4; dark blue, P value <2.47E-5. Suffix of “base” indicates the logistic regression model at baseline, “surv” for the survival analysis during the course, and “cont” for the linear mixed effect model for continuous outcome analyzed by linear mixed model. CONST, constipation; COGi, cognitive impairment; DEPR, depression; HY3, Hoehn and Yahr score; INS, insomnia; MMSE, Mini-Mental State Examination; MOCA, Montreal Cognitive Assessment; SEADL, the modified Schwab and England Activities of Daily Living Scale; SEADL70, the modified Schwab and England Activities of Daily Living Scale; SLEEP, daytime sleepiness; UPDRS, Unified Parkinson’s Disease Rating Scale or the Movement Disorder Society–revised UPDRS, scaled at the baseline (UPDRS1–3) or during the course.

FIG. 4.

Heatmap of the GBA and APOE variants associated with progression markers. Cream, P value >0.05; light green, P value <0.05; green, Bonferroni-corrected P value <0.05. Suffix of “base” indicates the logistic regression model at baseline, “surv” for the survival analysis during the course, and “cont” for the linear mixed effect model for continuous outcome analyzed by linear mixed model. CONST, constipation; COGi, cognitive impairment; DEPR, depression; HY3, Hoehn and Yahr score; INS, insomnia; MMSE, Mini-Mental State Examination; MOCA, Montreal Cognitive Assessment; SEADL, the modified Schwab and England Activities of Daily Living Scale; SEADL70, the modified Schwab and England Activities of Daily Living Scale; SLEEP, daytime sleepiness; UPDRS, Unified Parkinson’s Disease Rating Scale or the Movement Disorder Society–revised UPDRS, scaled at the baseline (UPDRS1–3) or during the course.