Adkar Shaunak S, Lynch Julie, Choi Ryan B, Roychowdhury Tanmoy, Judy Renae L, Paruchuri Kaavya, Go Dong-Chuan, Bamezai Sharika, Cabot John, Sorondo Sabina, Levin Michael G, Milewicz Dianna M, Willer Cristen J, Natarajan Pradeep, Pyarajan Saiju, Chang Kyong-Mi, Damrauer Scott, Tsao Phil, Skirboll Stephen, Leeper Nicholas J, Klarin Derek
Division of Vascular Surgery, Department of Surgery (S.S.A., J.C., S. Sorondo, N.J.L., D.K.), Stanford University School of Medicine, Palo Alto, CA.
Stanford Cardiovascular Institute, Stanford University, CA (S.S.A., S.B., J.C., S. Sorondo. P.T., N.J.L.).
Circ Genom Precis Med. 2025 Jun;18(3):e004626. doi: 10.1161/CIRCGEN.123.004626. Epub 2025 Apr 21.
The genetic risk of intracranial aneurysm (IA) development has been ascribed to the genetic risk of smoking exposure and hypertension. The relationship of IA to other cardiovascular traits and the contribution of IA risk loci to aberrant gene programs within cerebrovascular cell types remains unclear.
We performed a genome-wide association study in the Million Veteran Program and Finnish cohort study testing association of roughly 25 million DNA variants with unruptured IA (4694 cases and 877 091 controls) in individuals of European, African, and Hispanic ancestries. Meta-analysis with publicly available summary statistics generated a final cohort of 15 438 cases and 1 183 973 controls. We constructed a cerebrovascular single-nuclear RNA sequencing data set and integrated IA summary statistics to prioritize candidate causal cell types. We constructed a polygenic risk score to identify patients at risk of developing IA.
We identified 5 novel associations with IA, increasing the number of known susceptibility loci to 22. At these susceptibility loci, we prioritized 17 candidate causal genes. We found a significant positive genetic correlation of IA with coronary artery disease and abdominal aortic aneurysm. Integration of an IA gene set with cerebrovascular single-nuclear RNA sequencing data revealed a significant association with pericytes and smooth muscle cells. Finally, a polygenic risk score was significantly associated with IA across European (odds ratio, 1.87 [95% CI, 1.61-2.17]; =8.8×10), African (odds ratio, 1.62 [95% CI, 1.19-2.15]; =1.2×10), and Hispanic (odds ratio, 2.28 [95% CI, 1.47-3.38]; =1.0×10) ancestries.
Here, we identify 5 novel loci associated with IA. Integration of summary statistics with cerebrovascular single-nuclear RNA sequencing reveals an association of cell types involved in matrix production. We validated a polygenic risk score that predicts IA, controlling for demographic variables including smoking status and blood pressure. Our findings suggest that a deficit in matrix production may drive IA pathogenesis independent of hypertension and smoking.
颅内动脉瘤（IA）发生的遗传风险已归因于吸烟暴露和高血压的遗传风险。IA与其他心血管特征的关系以及IA风险位点对脑血管细胞类型内异常基因程序的贡献仍不清楚。
我们在百万退伍军人计划和芬兰队列研究中进行了一项全基因组关联研究，测试了约2500万个DNA变异与欧洲、非洲和西班牙裔血统个体中未破裂IA（4694例病例和877091例对照）的关联性。与公开可用的汇总统计数据进行荟萃分析，最终得到了一个包含15438例病例和1183973例对照的队列。我们构建了一个脑血管单核RNA测序数据集，并整合IA汇总统计数据以确定候选因果细胞类型的优先级。我们构建了一个多基因风险评分来识别有发生IA风险的患者。
我们确定了5个与IA相关的新关联，使已知的易感基因座数量增加到22个。在这些易感基因座上，我们确定了17个候选因果基因。我们发现IA与冠状动脉疾病和腹主动脉瘤之间存在显著的正遗传相关性。将IA基因集与脑血管单核RNA测序数据整合后发现与周细胞和平滑肌细胞存在显著关联。最后，多基因风险评分在欧洲人（优势比，1.87[95%CI，1.61 - 2.17]；P = 8.8×10⁻⁸）、非洲人（优势比，1.62[95%CI，1.19 - 2.15]；P = 1.2×10⁻²）和西班牙裔（优势比，2.28[95%CI，1.47 - 3.38]；P = 1.0×10⁻²）血统个体中与IA显著相关。
在此，我们确定了5个与IA相关的新基因座。将汇总统计数据与脑血管单核RNA测序整合后揭示了参与基质产生的细胞类型之间的关联。我们验证了一个预测IA的多基因风险评分，该评分控制了包括吸烟状况和血压在内的人口统计学变量。我们的研究结果表明，基质产生不足可能独立于高血压和吸烟驱动IA发病机制。
