Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, 1450 Biggy Street, Los Angeles, CA 90033, United States.
Biostatistics Division, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, 2001 North Soto Street, Los Angeles, CA 90033, United States.
Hum Mol Genet. 2024 Jan 7;33(2):170-181. doi: 10.1093/hmg/ddad174.
Stroke, characterized by sudden neurological deficits, is the second leading cause of death worldwide. Although genome-wide association studies (GWAS) have successfully identified many genomic regions associated with ischemic stroke (IS), the genes underlying risk and their regulatory mechanisms remain elusive. Here, we integrate a large-scale GWAS (N = 1 296 908) for IS together with molecular QTLs data, including mRNA, splicing, enhancer RNA (eRNA), and protein expression data from up to 50 tissues (total N = 11 588). We identify 136 genes/eRNA/proteins associated with IS risk across 60 independent genomic regions and find IS risk is most enriched for eQTLs in arterial and brain-related tissues. Focusing on IS-relevant tissues, we prioritize 9 genes/proteins using probabilistic fine-mapping TWAS analyses. In addition, we discover that blood cell traits, particularly reticulocyte cells, have shared genetic contributions with IS using TWAS-based pheWAS and genetic correlation analysis. Lastly, we integrate our findings with a large-scale pharmacological database and identify a secondary bile acid, deoxycholic acid, as a potential therapeutic component. Our work highlights IS risk genes/splicing-sites/enhancer activity/proteins with their phenotypic consequences using relevant tissues as well as identify potential therapeutic candidates for IS.
中风，以突发的神经功能缺损为特征，是全球第二大致死原因。尽管全基因组关联研究（GWAS）已经成功鉴定了许多与缺血性中风（IS）相关的基因组区域，但潜在的风险基因及其调控机制仍不清楚。在这里，我们整合了一项针对 IS 的大规模 GWAS（N=1296908），以及分子 QTL 数据，包括来自多达 50 种组织的 mRNA、剪接、增强子 RNA（eRNA）和蛋白质表达数据（总 N=11588）。我们在 60 个独立的基因组区域中鉴定出与 IS 风险相关的 136 个基因/eRNA/蛋白质，并发现 IS 风险在动脉和与大脑相关的组织中最富集于 eQTLs。在关注与 IS 相关的组织时，我们使用概率精细映射 TWAS 分析对 9 个基因/蛋白质进行了优先级排序。此外，我们发现使用基于 TWAS 的 pheWAS 和遗传相关性分析，血细胞特征，特别是网织红细胞，与 IS 具有共同的遗传贡献。最后，我们将我们的发现与一个大型药理学数据库整合，并鉴定出一种潜在的治疗成分——次级胆汁酸脱氧胆酸。我们的工作突出了使用相关组织的 IS 风险基因/剪接位点/增强子活性/蛋白质及其表型后果，并确定了 IS 的潜在治疗候选物。
