Center for Genomic Medicine, Massachusetts General Hospital, Boston (E.P.M., M.K.G., J.R., C.D.A.).
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA (E.P.M., M.K.G., J.R., C.D.A.).
Stroke. 2023 Apr;54(4):973-982. doi: 10.1161/STROKEAHA.122.041701. Epub 2023 Feb 17.
Intracerebral hemorrhage (ICH) has an estimated heritability of 29%. We developed a genomic risk score for ICH and determined its predictive power in comparison to standard clinical risk factors.
We combined genome-wide association data from individuals of European ancestry for ICH and related traits in a meta-genomic risk score ([metaGRS]; 2.6 million variants). We tested associations with ICH and its predictive performance in addition to clinical risk factors in a held-out validation dataset (842 cases and 796 controls). We tested associations with risk of incident ICH in the population-based UK Biobank cohort (486 784 individuals, 1526 events, median follow-up 11.3 years).
One SD increment in the metaGRS was significantly associated with 31% higher odds for ICH (95% CI, 1.16-1.48) in age-, sex- and clinical risk factor-adjusted models. The metaGRS identified individuals with almost 5-fold higher odds for ICH in the top score percentile (odds ratio, 4.83 [95% CI, 1.56-21.2]). Predictive models for ICH incorporating the metaGRS in addition to clinical predictors showed superior performance compared to the clinical risk factors alone (c-index, 0.695 versus 0.686). The metaGRS showed similar associations for lobar and nonlobar ICH, independent of the known risk locus for lobar ICH. In the UK Biobank, the metaGRS was associated with higher risk of incident ICH (hazard ratio, 1.15 [95% CI, 1.09-1.21]). The associations were significant within both a relatively high-risk population of antithrombotic medications users, as well as among a relatively low-risk population with a good control of vascular risk factors and no use of anticoagulants.
We developed and validated a genomic risk score that predicts lifetime risk of ICH beyond established clinical risk factors among individuals of European ancestry. Whether implementation of the score in risk prognostication models for high-risk populations, such as patients under antithrombotic treatment, could improve clinical decision making should be explored in future studies.
脑出血 (ICH) 的遗传率估计为 29%。我们开发了一种针对 ICH 的基因组风险评分，并确定了其与标准临床危险因素相比的预测能力。
我们在一个元基因组风险评分 (metaGRS; 260 万个变体) 中结合了欧洲血统个体的全基因组关联数据，用于 ICH 和相关特征。我们在一个保留的验证数据集 (842 例病例和 796 例对照) 中测试了与 ICH 的关联及其预测性能，以及与临床危险因素的关联。我们在基于人群的英国生物银行队列中测试了与 ICH 发病风险的关联 (486784 人，1526 例事件，中位随访 11.3 年)。
在年龄、性别和临床危险因素调整后的模型中，metaGRS 每增加一个标准差，ICH 的几率就会显著增加 31% (95%CI，1.16-1.48)。metaGRS 确定了最高评分百分位的个体，其 ICH 的几率几乎高出 5 倍 (优势比，4.83 [95%CI，1.56-21.2])。与临床危险因素相比，纳入 metaGRS 的 ICH 预测模型显示出优于临床危险因素的性能 (c 指数，0.695 与 0.686)。metaGRS 对大脑叶和非大脑叶 ICH 的相关性相似，与大脑叶 ICH 的已知风险基因座无关。在英国生物银行中，metaGRS 与较高的 ICH 发病风险相关 (风险比，1.15 [95%CI，1.09-1.21])。在使用抗血栓药物的高风险人群中，以及在血管危险因素控制良好且不使用抗凝剂的低风险人群中，这些相关性都具有统计学意义。
我们开发并验证了一种基因组风险评分，该评分可预测欧洲血统个体一生中的 ICH 风险，超出了已建立的临床危险因素。在未来的研究中，应探讨在高危人群 (如抗血栓治疗患者) 的风险预测模型中实施评分是否能改善临床决策。
