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Updated: Jul 19, 2025

Dynamic Digital Biomarkers of Motor and Cognitive Function in Parkinson's Disease
Published on: July 24, 2019
Genome-wide Analysis of Motor Progression in Parkinson Disease
Alejandro Martínez Carrasco1, Raquel Real1, Michael Lawton1
1From the Department of Clinical and Movement Neurosciences (A.M.C., R.R., L.W., H.R.M.), UCL Queen Square Institute of Neurology; UCL Movement Disorders Centre (A.M.C., R.R., L.W., H.R.M.), University College London, United Kingdom; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network (A.M.C., R.R., R.H.R. L.W., M.R., M.S. J.H., H.R.M.), Chevy Chase, MD; Population Health Sciences (M.L., Y.B.-S.), Bristol Medical School, University of Bristol; Genetics and Genomic Medicine (R.H.R., M.R.), UCL Great Ormond Street Institute of Child Health, University College London, United Kingdom; Department of Neurology (M.T.), Oslo University Hospital, Norway; Institute of Psychological Medicine and Clinical Neurosciences (N.W.), MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University; Faculty of Health (C.C.), University of Plymouth, United Kingdom; Sorbonne Université (J.-C.C.), Institut du Cerveau - Paris Brain Institute - ICM, INSERM, CNRS; Assistance Publique Hôpitaux de Paris (J.-C.C.), Department of Neurology, Hôpital Pitié-Salpêtrière, France; Division of Clinical Neurology (M.H.), Nuffield Department of Clinical Neurosciences; Oxford Parkinson's Disease Centre (M.H.), University of Oxford; School of Neuroscience and Psychology (D.G.), University of Glasgow; Department of Neurodegenerative Diseases (J.H., M.S.), UCL Queen Square Institute of Neurology; UK Dementia Research Institute (J.H., M.S.), University College London; Reta Lila Weston Institute (J.H., M.S.), UCL Queen Square Institute of Neurology; National Institute for Health Research (NIHR), University College London Hospitals Biomedical Research Centre (J.H.); Institute for Advanced Study (J.H.), The Hong Kong University of Science and Technology, Hong Kong SAR, China; and NIHR Great Ormond Street Hospital Biomedical Research Centre (M.R.), University College London, United Kingdom.
Background And Objectives:
The genetic basis of Parkinson disease (PD) motor progression is largely unknown. Previous studies of the genetics of PD progression have included small cohorts and shown a limited overlap with genetic PD risk factors from case-control studies. Here, we have studied genomic variation associated with PD motor severity and early-stage progression in large longitudinal cohorts to help to define the biology of PD progression and potential new drug targets.
Methods:
We performed a GWAS meta-analysis of early PD motor severity and progression up to 3 years from study entry. We used linear mixed-effect models with additive effects, corrected for age at diagnosis, sex, and the first 5 genetic principal components to assess variability in axial, limb, and total Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III scores.
Results:
We included 3,572 unrelated European ancestry patients with PD from 5 observational cohorts and 1 drug trial. The average AAO was 62.6 years (SD = 9.83), and 63% of participants were male. We found an average increase in the total MDS-UPDRS III score of 2.3 points/year. We identified an association between PD axial motor progression and variation at the GJA5 locus at 1q12 (β = -0.25, SE = 0.04, p = 3.4e-10). Exploration of the regulation of gene expression in the region (cis-expression quantitative trait loci [eQTL] analysis) showed that the lead variant was associated with expression of ACP6, a lysophosphatidic acid phosphatase that regulates mitochondrial lipid biosynthesis (cis-eQTL p-values in blood and brain RNA expression data sets: <10-14 in eQTLGen and 10-7 in PsychEncode).
Discussion:
Our study highlights the potential role of mitochondrial lipid homeostasis in the progression of PD, which may be important in establishing new drug targets that might modify disease progression.
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