Genome-wide association studies of cognitive and motor progression in Parkinson's disease

Abstract

BackgroundThere are currently no treatments that stop or slow the progression of Parkinsons disease (PD). Case-control genome-wide association studies (GWASs) have identified variants associated with disease risk, but not progression. ObjectiveTo identify genetic variants associated with PD progression in GWASs. MethodsWe analysed three large, longitudinal cohorts: Tracking Parkinsons, Oxford Discovery, and the Parkinsons Progression Markers Initiative. We included clinical data for 3,364 patients with 12,144 observations (mean follow-up 4.2 years). We used a new method in PD, following a similar approach in Huntingtons disease, where we combined multiple assessments using a principal components analysis to derive scores for composite, motor, and cognitive progression. These scores were analysed in linear regressions in GWASs. We also performed a targeted analysis of the 90 PD risk loci from the latest case-control meta-analysis. ResultsThere was no overlap between variants associated with PD risk, from case-control studies, and PD age at onset versus PD progression. The APOE {varepsilon}4 tagging variant, rs429358, was significantly associated with the rate of composite and cognitive progression in PD. No single variants were associated with motor progression. However in gene-based analysis, variation across ATP8B2, a phospholipid transporter related to vesicle formation, was nominally associated with motor progression (p=5.3 x 10-6). ConclusionsThis new method in PD improves measurement of symptom progression. We provide strong evidence that the APOE {varepsilon}4 allele drives progressive cognitive impairment in PD. We have also identified other loci of interest, such as ATP8B2 for motor progression, which need to be replicated in further studies.