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Lookup NU author(s): Professor Camille CarrollORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© 2023 Lippincott Williams and Wilkins. All rights reserved. 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.
Author(s): Carrasco AM, Real R, Lawton M, Reynolds RH, Tan M, Wu L, Williams N, Carroll C, Corvol J-C, Hu M, Grosset D, Hardy J, Ryten M, Ben-Shlomo Y, Shoai M, Morris HR
Publication type: Article
Publication status: Published
Journal: Neurology: Genetics
Year: 2023
Volume: 9
Issue: 5
Print publication date: 01/10/2023
Online publication date: 08/08/2023
Acceptance date: 08/06/2023
Date deposited: 11/02/2025
ISSN (electronic): 2376-7839
Publisher: Lippincott Williams and Wilkins
URL: https://doi.org/10.1212/NXG.0000000000200092
DOI: 10.1212/NXG.0000000000200092
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