多基因风险评分增强中风亚型分类。
Polygenic Risk Scores Augment Stroke Subtyping.
作者信息
Li Jiang, Chaudhary Durgesh P, Khan Ayesha, Griessenauer Christoph, Carey David J, Zand Ramin, Abedi Vida
机构信息
Department of Molecular and Functional Genomics (J.L., D.J.C., V.A.), Weis Center for Research, Geisinger Health System; Neuroscience Institute (D.P.C., A.K., C.G., R.Z.), Geisinger Health System, Danville, PA; Biocomplexity Institute (V.A.), Virginia Tech, Blacksburg, VA; and Research Institute of Neurointervention (C.G.), Paracelsus Medical University, Salzburg, Austria.
出版信息
Neurol Genet. 2021 Mar 9;7(2):e560. doi: 10.1212/NXG.0000000000000560. eCollection 2021 Apr.
OBJECTIVE
To determine whether the polygenic risk score (PRS) derived from MEGASTROKE is associated with ischemic stroke (IS) and its subtypes in an independent tertiary health care system and to identify the PRS derived from gene sets of known biological pathways associated with IS.
METHODS
Controls (n = 19,806/7,484, age ≥69/79 years) and cases (n = 1,184/951 for discovery/replication) of acute IS with European ancestry and clinical risk factors were identified by leveraging the Geisinger Electronic Health Record and chart review confirmation. All Geisinger MyCode patients with age ≥69/79 years and without any stroke-related diagnostic codes were included as low risk control. Genetic heritability and genetic correlation between Geisinger and MEGASTROKE (EUR) were calculated using the summary statistics of the genome-wide association study by linkage disequilibrium score regression. All PRS for any stroke (AS), any ischemic stroke (AIS), large artery stroke (LAS), cardioembolic stroke (CES), and small vessel stroke (SVS) were constructed by PRSice-2.
RESULTS
A moderate heritability (10%-20%) for Geisinger sample as well as the genetic correlation between MEGASTROKE and the Geisinger cohort was identified. Variation of all 5 PRS significantly explained some of the phenotypic variations of Geisinger IS, and the increased by raising the cutoff for the age of controls. PRSLAS, PRSCES, and PRSSVS derived from low-frequency common variants provided the best fit for modeling ( = 0.015 for PRSLAS). Gene sets analyses highlighted the association of PRS with Gene Ontology terms (vascular endothelial growth factor, amyloid precursor protein, and atherosclerosis). The PRSLAS, PRSCES, and PRSSVS explained the most variance of the corresponding subtypes of Geisinger IS suggesting shared etiologies and corroborated Geisinger TOAST subtyping.
CONCLUSIONS
We provide the first evidence that PRSs derived from MEGASTROKE have value in identifying shared etiologies and determining stroke subtypes.
目的
在一个独立的三级医疗保健系统中，确定源自MEGASTROKE研究的多基因风险评分（PRS）是否与缺血性卒中（IS）及其亚型相关，并识别源自与IS相关的已知生物学途径基因集的PRS。
方法
利用盖辛格电子健康记录并经病历审查确认，纳入具有欧洲血统且有临床风险因素的急性IS对照者（n = 19806/7484，年龄≥69/79岁）和病例（n = 1184/951用于发现/重复验证）。所有年龄≥69/79岁且无任何卒中相关诊断代码的盖辛格MyCode患者被纳入作为低风险对照。利用连锁不平衡评分回归的全基因组关联研究汇总统计数据，计算盖辛格研究与MEGASTROKE（欧洲人）之间的遗传力和遗传相关性。通过PRSice-2构建所有卒中（AS）、任何缺血性卒中（AIS）、大动脉卒中（LAS）、心源性栓塞性卒中（CES）和小血管卒中（SVS）的PRS。
结果
确定了盖辛格样本的中度遗传力（10%-20%）以及MEGASTROKE与盖辛格队列之间的遗传相关性。所有5种PRS的变异显著解释了盖辛格IS的一些表型变异，并且通过提高对照年龄的临界值而增加。源自低频常见变异的PRSLAS、PRSCES和PRSSVS对模型的拟合效果最佳（PRSLAS的 = 0.015）。基因集分析突出了PRS与基因本体术语（血管内皮生长因子、淀粉样前体蛋白和动脉粥样硬化）的关联。PRSLAS、PRSCES和PRSSVS解释了盖辛格IS相应亚型的最大变异，提示病因相同，并证实了盖辛格TOAST分型。
结论
我们提供了首个证据，表明源自MEGASTROKE的PRS在识别共同病因和确定卒中亚型方面具有价值。
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