Martínez Carrasco, Alejandro, Real, Raquel, Lawton, Michael, Hertfelder Reynolds, Regina, Tan, Manuela, Wu, Lesley, Williams, Nigel  ORCID: https://orcid.org/0000-0003-1177-6931, 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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Abstract
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: | Professional Services > Advanced Research Computing @ Cardiff (ARCCA) Research Institutes & Centres > MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Schools > Medicine |
| Publisher: | Lippincott, Williams & Wilkins |
| ISSN: | 2376-7839 |
| Date of First Compliant Deposit: | 5 October 2023 |
| Date of Acceptance: | 8 June 2023 |
| Last Modified: | 06 Jun 2025 13:26 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/162979 |
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