Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
State Key Laboratory of Genetic Engineering, School of life Sciences, Human Phenome Institute, Fudan University, Shanghai, China.
BMC Neurol. 2024 Jul 25;24(1):258. doi: 10.1186/s12883-024-03759-0.
Cerebral artery dissection (CeAD) is a rare but serious disease. Genetic risk assessment for CeAD is lacking in Chinese population. We performed genome-wide association study (GWAS) and computed polygenic risk score (PRS) to explore genetic susceptibility factors and prediction model of CeAD based on patients in Huashan Hospital.
A total of 210 CeAD patients and 280 controls were enrolled from June 2017 to September 2022 in Department of Neurology, Huashan Hospital, Fudan University. We performed GWAS to identify genetic variants associated with CeAD in 140 CeAD patients and 210 control individuals according to a case and control 1:1.5 design rule in the training dataset, while the other 70 patients with CeAD and 70 controls were used as validation. Then Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) enrichment analyses were utilized to identify the significant pathways. We constructed a PRS by capturing all independent GWAS SNPs in the analysis and explored the predictivity of PRS, age, and sex for CeAD.
Through GWAS analysis of the 140 cases and 210 controls in the training dataset, we identified 13 leading SNPs associated with CeAD at a genome-wide significance level of P < 5 × 10. Among them, 10 SNPs were annotated in or near (in the upstream and downstream regions of ± 500Kb) 10 functional genes. rs34508376 (OR2L13) played a suggestive role in CeAD pathophysiology which was in line with previous observations in aortic aneurysms. The other nine genes were first-time associations in CeAD cases. GO enrichment analyses showed that these 10 genes have known roles in 20 important GO terms clustered into two groups: (1) cellular biological processes (BP); (2) molecular function (MF). We used genome-wide association data to compute PRS including 32 independent SNPs and constructed predictive model for CeAD by using age, sex and PRS as predictors both in training and validation test. The area under curve (AUC) of PRS predictive model for CeAD reached 99% and 95% in the training test and validation test respectively, which were significantly larger than the age and sex models of 83% and 86%.
Our study showed that ten risk loci were associated with CeAD susceptibility, and annotated functional genes had roles in 20 important GO terms clustered into biological process and molecular function. The PRS derived from risk variants was associated with CeAD incidence after adjusting for age and sex both in training test and validation.
大脑动脉夹层（CeAD）是一种罕见但严重的疾病。中国人群缺乏 CeAD 的遗传风险评估。我们进行了全基因组关联研究（GWAS）和计算多基因风险评分（PRS），以探索基于华山医院患者的 CeAD 的遗传易感性因素和预测模型。
本研究共纳入 2017 年 6 月至 2022 年 9 月在复旦大学华山医院神经内科的 210 例 CeAD 患者和 280 例对照者。我们根据病例对照 1:1.5 的设计规则，在训练数据集的 140 例 CeAD 患者和 210 例对照者中进行了 GWAS，以鉴定与 CeAD 相关的遗传变异，而其他 70 例 CeAD 患者和 70 例对照者则用于验证。然后，我们利用京都基因与基因组百科全书（KEGG）途径和基因本体论（GO）富集分析来确定显著的途径。我们通过捕获分析中所有独立的 GWAS SNP 构建了一个 PRS，并探讨了 PRS、年龄和性别对 CeAD 的预测能力。
通过对训练数据集中的 140 例病例和 210 例对照者进行 GWAS 分析，我们鉴定出了 13 个与 CeAD 相关的全基因组显著水平的 P < 5×10 的 SNP。其中，10 个 SNP 注释在或接近（在 ± 500Kb 的上下游区域）10 个功能基因内或附近。rs34508376（OR2L13）在 CeAD 病理生理学中起提示作用，与先前在主动脉瘤中的观察结果一致。其他九个基因是 CeAD 病例中的首次关联。GO 富集分析表明，这 10 个基因在聚类为两组的 20 个重要 GO 术语中具有已知作用：（1）细胞生物学过程（BP）；（2）分子功能（MF）。我们使用全基因组关联数据计算了包括 32 个独立 SNP 的 PRS，并使用年龄、性别和 PRS 作为预测因子，在训练和验证测试中构建了 CeAD 的预测模型。PRS 预测模型对 CeAD 的 AUC 在训练测试和验证测试中分别达到 99%和 95%，明显大于年龄和性别模型的 83%和 86%。
我们的研究表明，十个风险位点与 CeAD 易感性相关，注释的功能基因在聚类为生物学过程和分子功能的 20 个重要 GO 术语中具有作用。在调整年龄和性别后，来自风险变异的 PRS 与训练测试和验证中的 CeAD 发生率相关。
