帕金森病运动亚型的全基因组关联研究荟萃分析
Genome-Wide Association Study Meta-Analysis for Parkinson Disease Motor Subtypes.
作者信息
Alfradique-Dunham Isabel, Al-Ouran Rami, von Coelln Rainer, Blauwendraat Cornelis, Hill Emily, Luo Lan, Stillwell Amanda, Young Emily, Kaw Anita, Tan Manuela, Liao Calwing, Hernandez Dena, Pihlstrom Lasse, Grosset Donald, Shulman Lisa M, Liu Zhandong, Rouleau Guy A, Nalls Mike, Singleton Andrew B, Morris Huw, Jankovic Joseph, Shulman Joshua M
机构信息
Department of Neurology (I.A.-D., E.H., L.L., A.S., E.Y., A.K., J.J., J.M.S.), Baylor College of Medicine, Houston, TX; Department of Pediatrics (R.A.-O., Z.L.), Baylor College of Medicine, Houston, TX; Jan and Dan Duncan Neurological Research Institute (R.A.-O., Z.L., J.M.S.), Texas Childrens Hospital, Houston, TX; Department of Neurology (R.C., L.M.S.), University of Maryland School of Medicine, Baltimore, MD; Molecular Genetics Section (C.B., D.H., M.N., A.B.S.), Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD; Department of Clinical and Movement Neurosciences (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; UCL Movement Disorders Centre (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; Montreal Neurological Institute (C.L., G.A.R.), Montréal, Quebec, Canada; Department of Human Genetics (C.L., G.A.R.), McGill University, Montréal, Quebec, Canada; Department of Neurology (L.P.), Oslo University Hospital, Oslo, Norway; Department of Neurology (D.G.), Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK; Department of Neurology and Neurosurgery (G.A.R.), McGill University, Montréal, Quebec, Canada; Data Tecnica International (M.N.), Glen Echo, MD; Parkinsons Disease Center and Movement Disorders Clinic (J.J., J.M.S.), Department of Neurology, Baylor College of Medicine, Houston, TX; Department of Molecular & Human Genetics (J.M.S.), Baylor College of Medicine, Houston, TX; and Department of Neuroscience (J.M.S.), Baylor College of Medicine, Houston, TX.
出版信息
Neurol Genet. 2021 Jan 28;7(2):e557. doi: 10.1212/NXG.0000000000000557. eCollection 2021 Apr.
OBJECTIVE
To discover genetic determinants of Parkinson disease (PD) motor subtypes, including tremor dominant (TD) and postural instability/gait difficulty (PIGD) forms.
METHODS
In 3,212 PD cases of European ancestry, we performed a genome-wide association study (GWAS) examining 2 complementary outcome traits derived from the Unified Parkinson's Disease Rating Scale, including dichotomous motor subtype (TD vs PIGD) or a continuous tremor/PIGD score ratio. Logistic or linear regression models were adjusted for sex, age at onset, disease duration, and 5 ancestry principal components, followed by meta-analysis.
RESULTS
Among 71 established PD risk variants, we detected multiple suggestive associations with PD motor subtype, including (, = 0.01, = 0.03), (, = 0.02, = 0.01), (, = 0.02), (, = 0.02), and (, = 0.02). A PD genetic risk score integrating all 71 PD risk variants was also associated with subtype ratio ( = 0.026, ß = -0.04, 95% confidence interval = -0.07-0). Based on top results of our GWAS, we identify a novel suggestive association at the locus (rs2301857, = 6.6 × 10), which harbors an independent risk allele for essential tremor.
CONCLUSIONS
Multiple PD risk alleles may also modify clinical manifestations to influence PD motor subtype. The discovery of a novel variant at suggests a possible overlap between genetic risk for essential tremor and tremor-dominant PD.
目的
发现帕金森病（PD）运动亚型的遗传决定因素，包括震颤为主型（TD）和姿势不稳/步态障碍（PIGD）型。
方法
在3212例欧洲血统的PD患者中，我们进行了一项全基因组关联研究（GWAS），检测了源自统一帕金森病评定量表的2个互补结局特征，包括二分法运动亚型（TD与PIGD）或连续的震颤/PIGD评分比值。逻辑回归或线性回归模型对性别、发病年龄、病程和5个祖先主成分进行了校正，随后进行荟萃分析。
结果
在71个已确定的PD风险变异中，我们检测到多个与PD运动亚型的潜在关联，包括（， = 0.01， = 0.03）、（， = 0.02， = 0.01）、（， = 0.02）、（， = 0.02）和（， = 0.02）。整合所有71个PD风险变异的PD遗传风险评分也与亚型比值相关（ = 0.026，β = -0.04，95%置信区间 = -0.07 - 0）。基于我们GWAS的顶级结果，我们在 位点（rs2301857， = 6.6 × 10）发现了一个新的潜在关联，该位点含有特发性震颤的一个独立风险等位基因。
结论
多个PD风险等位基因也可能改变临床表现以影响PD运动亚型。在 位点发现的一个新变异提示特发性震颤和震颤为主型PD的遗传风险可能存在重叠。
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