Genome‐Wide Association Studies of Cognitive and Motor Progression in Parkinson's Disease

Manuela Tan(Queen Mary University of London), Michael Lawton(University of Bristol), Edwin Jabbari(Queen Mary University of London), Regina H. Reynolds(MRC Prion Unit), Hirotaka Iwaki(National Institutes of Health), Cornelis Blauwendraat(National Institutes of Health), Sofia Kanavou(University of Bristol), Miriam I. Pollard(Queen Mary University of London), Leon Hubbard(Cardiff University), Naveed Malek(Queen Elizabeth University Hospital), Katherine A. Grosset(Queen Elizabeth University Hospital), Sarah Marrinan(Newcastle Hospitals - Campus for Ageing and Vitality), Nin Bajaj(University of Nottingham), Roger A. Barker(Wellcome/MRC Cambridge Stem Cell Institute), David J. Burn(Newcastle University), Catherine Bresner(Cardiff University), Thomas Foltynie(Queen Mary University of London), Nicholas Wood(Queen Mary University of London), Caroline H. Williams‐Gray(University of Cambridge), John Hardy(Hong Kong University of Science and Technology), Michael A. Nalls(National Institutes of Health), Andrew Singleton(National Institutes of Health), Nigel Williams(Cardiff University), Yoav Ben‐Shlomo(University of Bristol), Michele T.M. Hu(Nuffield Orthopaedic Centre), Donald G. Grosset(Queen Elizabeth University Hospital), Maryam Shoai(UK Dementia Research Institute), Huw R. Morris(Queen Mary University of London)
Movement Disorders
October 28, 2020
10.1002/mds.28342
Cited by 171Open Access
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Abstract

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. The objective of the current study was to identify genetic variants associated with PD progression. Methods We analyzed 3 large longitudinal cohorts: Tracking Parkinson's, Oxford Discovery, and the Parkinson's Progression Markers Initiative. We included clinical data for 3364 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, in which we combined multiple assessments using a principal components analysis to derive scores for composite, motor, and cognitive progression. These scores were analyzed in linear regression 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 case–control studies, and PD age at onset versus PD progression. The APOE ε4 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 = 5.3 × 10 −6 ). Conclusions We provide early evidence that this new method in PD improves measurement of symptom progression. We show that the APOE ε4 allele drives progressive cognitive impairment in PD. Replication of this method and results in independent cohorts are needed. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

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