帕金森病运动进展的全基因组分析
Genome-wide Analysis of Motor Progression in Parkinson Disease.
作者信息
Martínez Carrasco Alejandro, Real Raquel, Lawton Michael, Hertfelder Reynolds Regina, Tan Manuela, Wu Lesley, Williams Nigel, Carroll Camille, Corvol Jean-Christophe, Hu Michele, Grosset Donald, Hardy John, Ryten Mina, Ben-Shlomo Yoav, Shoai Maryam, Morris Huw R
机构信息
From 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.
出版信息
Neurol Genet. 2023 Aug 8;9(5):e200092. doi: 10.1212/NXG.0000000000200092. eCollection 2023 Oct.
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 locus at 1q12 (β = -0.25, SE = 0.04, = 3.4e). Exploration of the regulation of gene expression in the region (-expression quantitative trait loci [eQTL] analysis) showed that the lead variant was associated with expression of , a lysophosphatidic acid phosphatase that regulates mitochondrial lipid biosynthesis (cis-eQTL -values in blood and brain RNA expression data sets: <10 in eQTLGen and 10 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.
背景与目的
帕金森病（PD）运动进展的遗传基础在很大程度上尚不清楚。先前关于PD进展遗传学的研究纳入的队列规模较小，且与病例对照研究中的遗传PD风险因素重叠有限。在此，我们在大型纵向队列中研究了与PD运动严重程度和早期进展相关的基因组变异，以帮助确定PD进展的生物学机制和潜在的新药物靶点。
方法
我们对研究入组后3年内的早期PD运动严重程度和进展进行了全基因组关联研究（GWAS）荟萃分析。我们使用具有加性效应的线性混合效应模型，并对诊断时的年龄、性别和前5个遗传主成分进行校正，以评估轴向、肢体和总运动障碍协会统一帕金森病评定量表（MDS-UPDRS）III评分的变异性。
结果
我们纳入了来自5个观察性队列和1项药物试验的3572名无亲缘关系的欧洲血统PD患者。平均发病年龄为62.6岁（标准差=9.83），63%的参与者为男性。我们发现MDS-UPDRS III总分平均每年增加2.3分。我们确定了PD轴向运动进展与1q12位点变异之间的关联（β=-0.25，标准误=0.04，P=3.4e）。对该区域基因表达调控的探索（表达数量性状位点[eQTL]分析）表明，领先变异与一种调节线粒体脂质生物合成的溶血磷脂酸磷酸酶的表达相关（血液和脑RNA表达数据集中的顺式eQTL P值：eQTLGen中<10，PsychEncode中<10）。
讨论
我们的研究突出了线粒体脂质稳态在PD进展中的潜在作用，这对于建立可能改变疾病进展的新药物靶点可能很重要。
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