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.

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.

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 R² 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 (R² = 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.

We provide the first evidence that PRSs derived from MEGASTROKE have value in identifying shared etiologies and determining stroke subtypes.

确定源自 MEGASTROKE 的多基因风险评分 (PRS) 是否与独立的三级医疗保健系统中的缺血性中风 (IS) 及其亚型相关，并确定源自与 IS 相关的已知生物途径基因组的 PRS。

通过利用 Geisinger 电子健康记录和图表审查，确定了具有欧洲血统和临床风险因素的急性 IS 对照（n = 19,806/7,484，年龄 ≥69/79 岁）和病例（n = 1,184/951，用于发现/复制）确认。所有年龄≥69/79 岁且没有任何中风相关诊断代码的 Geisinger MyCode 患者均被纳入低风险控制。Geisinger 和 MEGASTROKE (EUR) 之间的遗传遗传力和遗传相关性通过连锁不平衡评分回归使用全基因组关联研究的汇总统计数据进行计算。任何中风 (AS)、任何缺血性中风 (AIS)、大动脉中风 (LAS)、心源性中风 (CES) 和小血管中风 (SVS) 的所有 PRS 均由 PRSice-2 构建。

确定了 Geisinger 样本的中等遗传力 (10%–20%) 以及 MEGASTROKE 和 Geisinger 队列之间的遗传相关性。所有 5 个 PRS 的变化显着解释了 Geisinger IS 的一些表型变化，并且R ²通过提高对照年龄的截止值而增加。源自低频常见变体的 PRSLAS、PRSCES 和 PRSSVS 为建模提供了最佳拟合（R ²= 0.015 对于 PRSLAS）。基因组分析强调了 PRS 与基因本体论术语（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 Geisinger IS 相应亚型的最大差异，表明共同的病因并证实了 Geisinger TOAST 亚型。

我们提供了第一个证据表明源自 MEGASTROKE 的 PRS 在识别共同病因和确定中风亚型方面具有价值。