Year: 2023
Type: article
Study design: Observational Study
Abstract: ABSTRACT Importance There is a pressing need to understand the biology of Parkinson’s disease (PD) progression and to identify biological pathways as possible therapeutic targets. Objective To identify genomic variation associated with PD motor presentation and early stage progression. Design GWAS meta-analysis of early PD motor progression, from multiple longitudinal cohorts, using MDS-UPDRS III clinical assessments. Setting Multicentre Participants 3572 unrelated European ancestry individuals diagnosed with PD from 6 studies. Main Outcomes and Measures Linear mixed effect models under an additive model corrected for age at diagnosis, gender, and the first 5 genetic principal components (PCs), with axial, limb, and total MDS-UPDRS III as outcomes of the model. Results We identified an association between the PD axial rate of progression and variation at the GJA5 locus at 1q12 (Beta = -0.25, SE = 0.04, P = 3.4e-10). Exploration of the regulation of gene expression in the region (cis-eQTL analysis) showed that the lead variant was associated with expression of ACP6 , a lysophosphatidic acid phosphatase that regulates mitochondrial lipid biosynthesis (cis-eQTLs p-values in blood and brain RNA expression datasets: < 10 −8 in eQTLGen and 10 −7 in PsychEncode). In addition, we found a nominal association between axial motor presentation and the MAD1L1 gene at 7q21.11 (Beta = 0.54, SE = 0.11, P = 1.6e-7), a gene previously associated with neuropsychiatric disease, and in the long non-coding RNA LINC00511 at 17q21.31 (Beta = -0.62, SE = 0.11, P = 6.3e-8). Further functional annotation allowed us to nominate the likely causal variants and determine that variants at 7q21.11 may be related to dysregulation of MAD1L1 expression. Variants at LINC00511 may cause a disruption of a distal epigenetic regulation of SOX9 through an anchored chromatin loop. Conclusions and Relevance Our large multicentre study sheds new light on the genetic architecture of PD progression, which is distinct from PD susceptibility. Our study highlights the potential role of mitochondrial lipid homeostasis in the progression of PD, which may be important in establishing new drug targets to tackle disease progression.
Source: Neurology Genetics
Institutions: University of Bristol, Aligning Science Across Parkinson's, UCL Queen Square Institute of Neurology, University College London, Oslo University Hospital, Cardiff University, University of Plymouth, Centre National de la Recherche Scientifique, Inserm, Sorbonne Université, Institut des Sciences Moléculaires, Assistance Publique – Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Institut du Cerveau, University of Oxford, University of Glasgow, NIHR Great Ormond Street Hospital Biomedical Research Centre, UK Dementia Research Institute
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,300
Funders: Foundation for the National Institutes of Health, Michael J. Fox Foundation for Parkinson's Research, Pfizer, Sanofi, Biogen, Celgene, NHS Greater Glasgow and Clyde, PSP Association, Acorda Therapeutics, University Hospitals Plymouth NHS Trust, Alzheimer's Society, Verily Life Sciences, National Institute for Health and Care Research, Parkinson's UK, University College London, University of Oxford, European Commission, Agence Nationale de la Recherche, Assistance Publique - Hôpitaux de Paris, Edmond J. Safra Philanthropic Foundation, Hong Kong University of Science and Technology, Agence Nationale de Sécurité du Médicament et des Produits de Santé, Association France Parkinson, Servier, H. Lundbeck A/S, Idorsia Pharmaceuticals, UK Dementia Research Institute, Neurosciences Foundation, Britannia Pharmaceuticals, National Institutes of Health, Horizon 2020 Framework Programme, Otsuka Pharmaceutical Development and Commercialization, Medical Research Council, Economic and Social Research Council, Great Ormond Street Institute of Child Health, NIHR Oxford Biomedical Research Centre, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute on Drug Abuse, National Human Genome Research Institute, NIH Office of the Director, National Cancer Institute, National Institute of Neurological Disorders and Stroke, Common Fund
OpenAlex ID: W4385650789