Objective: To identify genetic variants associated with composite (cross-domain), motor, and cognitive progression in Parkinson’s disease (PD).

Background: Case-control genome-wide association studies (GWASs) in PD have identified 90 variants associated with disease risk¹. However, in order to understand the biology of disease progression, it is necessary to also study disease phenotypes within PD patients. Progression of clinical signs in PD can be measured in many different ways. Therefore, combining multiple measures may improve the accuracy of measuring progression, as shown in the Huntington’s disease progression GWAS².

Method: We analysed three large, longitudinal, prospective cohorts with systematic clinical data collection: Tracking Parkinson’s, Oxford Discovery, and the Parkinson’s Progression Markers Initiative. In total, we included clinical data for 3,364 PD patients with 12,144 observations over 72 months (mean follow-up 4.2 years). We used a new method in PD progression, following a similar approach in Huntington’s disease, where we combined multiple motor and cognitive assessments using principal components analysis to derive scores for composite, motor, and cognitive progression. These scores were analysed in linear regression GWASs, adjusting for cohort and 5 genetic principal components. We also performed a targeted analysis of the 90 PD risk loci from the latest case-control meta-analysis by extracting results of these SNPs from the progression GWASs.

Results: There was no overlap between variants associated with PD risk and PD progression. The APOE e4 tagging variant, rs429358, was significantly associated with the rate of composite progression (p = 1.32 x 10^-8) and cognitive progression (p = 2.88 x 10^-14) in PD. There were no single variants that were associated with the rate of motor progression in PD. However in gene-based analysis, variation across ATP8B2, a phospholipid transporter related to vesicle formation, was nominally associated with motor progression (p = 3.8 x 10^-6).

Conclusion: This new method in PD improves measurement of symptom progression. Consistent with recent work in animal models, we provide strong evidence that APOE e4 allele drives progressive cognitive impairment in PD. We have also reported other possible genes and loci of interest which need to be replicated in further studies.

References: 1. Nalls MA, Blauwendraat C, Vallerga CL, et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurol. 2019;18(12):1091-1102. doi:10.1016/S1474-4422(19)30320-5 2. Hensman-Moss DJ, Pardiñas AF, Langbehn D, et al. Identification of genetic variants associated with Huntington’s disease progression. Lancet Neurol. 2017;16(9):701-711. doi:10.1016/S1474-4422(17)30161-8

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genome-wide-association-studies-of-progression-in-parkinsons-disease/