Wang Min, Xu Chong, Du Xiaoshan, Zhu Tian, Yang Xitong, Duan Fuhui, Wang Guangyan, Zuo Yongchun, Chen Huaqiu, Wang Guangming
School of Clinical Medicine, Dali University, Dali, Yunnan 671000, China.
Department of Geriatrics, South District of Hefei First People's Hospital, Hefei, Anhui Province 230000, China.
Mol Ther Nucleic Acids. 2025 Jul 17;36(3):102633. doi: 10.1016/j.omtn.2025.102633. eCollection 2025 Sep 9.
Ischemic stroke (IS) is a major cause of disability and mortality, but its genetic basis remains poorly understood. This study integrates data from three large-scale genome-wide association studies (GWASs), the GWAS Catalog, MEGASTROKE, and Open GWAS, to identify novel genetic loci linked to IS. Our meta-analysis revealed 124 new IS-associated loci, with enrichment in genes involved in cerebrovascular function, inflammation, and metabolism. Candidate genes like , , and are linked to lipid metabolism, immune response, and iron metabolism, indicating diverse pathogenic mechanisms in IS. Further analyses, including expression quantitative trait locus (eQTL) and protein quantitative trait locus (pQTL), confirmed the relevance of these genes in the brain. Mendelian randomization and colocalization analyses highlighted seven genes with potential causal relationships to IS. Single-cell RNA sequencing identified differential gene expression in endothelial cells, implicating these genes in vascular dysfunction. Functional validation in knockout mouse models showed HSD17B12's role in fatty acid metabolism, linking it to cerebrovascular diseases. We also developed StrokeGene, an intelligent assistant based on large language models (LLMs) to aid IS genetic research. StrokeGene offers insights into IS pathophysiology. Collectively, these findings substantially advance the understanding of IS genetics and provide a foundation for precision medicine strategies in stroke prevention and treatment.
缺血性中风（IS）是导致残疾和死亡的主要原因，但其遗传基础仍知之甚少。本研究整合了来自三项大规模全基因组关联研究（GWAS）的数据，即GWAS Catalog、MEGASTROKE和Open GWAS，以确定与IS相关的新基因位点。我们的荟萃分析揭示了124个新的IS相关位点，这些位点在参与脑血管功能、炎症和代谢的基因中富集。诸如 、 和 等候选基因与脂质代谢、免疫反应和铁代谢相关，表明IS存在多种致病机制。进一步的分析，包括表达定量性状位点（eQTL）和蛋白质定量性状位点（pQTL），证实了这些基因在大脑中的相关性。孟德尔随机化和共定位分析突出了七个与IS有潜在因果关系的基因。单细胞RNA测序确定了内皮细胞中的差异基因表达，表明这些基因与血管功能障碍有关。基因敲除小鼠模型中的功能验证表明HSD17B12在脂肪酸代谢中的作用，将其与脑血管疾病联系起来。我们还开发了StrokeGene，这是一种基于大语言模型（LLM）的智能助手，以辅助IS遗传研究。StrokeGene为IS病理生理学提供了见解。总体而言，这些发现极大地推进了对IS遗传学的理解，并为中风预防和治疗中的精准医学策略奠定了基础。
