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

Manuela M X Tan, Michael A Lawton, Edwin Jabbari, Regina H Reynolds, Hirotaka Iwaki, Cornelis Blauwendraat, Sofia Kanavou, Miriam I Pollard, Leon Hubbard, Naveed Malek, Katherine A Grosset, Sarah L Marrinan, Nin Bajaj, Roger A Barker, David J Burn, Catherine Bresner, Thomas Foltynie, Nicholas W. Wood, Caroline H. Williams-Gray, John HardyMichael A Nalls, Andrew B Singleton, Nigel M Williams, Yoav Ben-Shlomo, Michele T M Hu, Donald G Grosset, Maryam Shoai, Huw R Morris

Research output: Contribution to journalArticle (Academic Journal)

Abstract

Background: There are currently no treatments that stop or slow the progression of Parkinson’s disease (PD). Case-control genome-wide association studies have identified variants associated with disease risk, but not progression.

Objective: To identify genetic variants associated with PD progression.

Methods: We analysed three large, longitudinal cohorts: Tracking Parkinson’s, Oxford Discovery, and the Parkinson’s 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 Huntington’s 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 genome-wide association studies. We also performed a targeted analysis of the 90 PD risk loci from the latest case-control meta-analysis.

Results: There was no overlap between variants associated with PD risk, from case75 control studies, and PD age at onset versus PD progression. The APOE 4 tagging variant, rs429358, was significantly associated with composite and cognitive progression in PD. Conditional analysis revealed several independent signals in the APOE locus for cognitive progression. No single variants were associated with motor progression. However in gene-based analysis, ATP8B2, a phospholipid transporter related to vesicle formation, was nominally associated with motor progression (p=5.3x10-6 81 ).

Conclusions: We provide early evidence that this new method in PD improves measurement of symptom progression. We show that the APOE 4 allele drives progressive cognitive impairment in PD. Replication of this method and results in independent cohorts is needed.
Original languageEnglish
JournalMovement Disorders
Publication statusAccepted/In press - 6 Oct 2020

Keywords

  • Parkinson's disease
  • genetics
  • progression
  • genome-wide association study

Cite this

Tan, M. M. X., Lawton, M. A., Jabbari, E., Reynolds, R. H., Iwaki, H., Blauwendraat, C., Kanavou, S., Pollard, M. I., Hubbard, L., Malek, N., Grosset, K. A., Marrinan, S. L., Bajaj, N., Barker, R. A., Burn, D. J., Bresner, C., Foltynie, T., Wood, N. W., Williams-Gray, C. H., ... Morris, H. R. (Accepted/In press). Genome-wide association studies of cognitive and motor progression in Parkinson's disease. Movement Disorders.