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Genome-wide analysis of motor progression in parkinson disease

Martínez Carrasco, Alejandro, Real, Raquel, Lawton, Michael, Hertfelder Reynolds, Regina, Tan, Manuela, Wu, Lesley, Williams, Nigel ORCID:, Carroll, Camille, Corvol, Jean-Christophe, Hu, Michele, Grosset, Donald, Hardy, John, Ryten, Mina, Ben-Shlomo, Yoav, Shoai, Maryam and Morris, Huw R. 2023. Genome-wide analysis of motor progression in parkinson disease. Neurology Genetics 9 (5) , e200092. 10.1212/NXG.0000000000200092

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Lippincott, Williams & Wilkins
ISSN: 2376-7839
Date of First Compliant Deposit: 5 October 2023
Date of Acceptance: 8 June 2023
Last Modified: 07 Oct 2023 03:29

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