Qian Yuyang, Wang Jianhua, Wang Bo, Wang Wenbin, Li Peng, Zhao Zhenhao, Jiang Yuan, Ren He, Huang Dandan, Yang Yang, Zhao Zhongfang, Zhang Lei, Shi Jiandang, Li Mulin Jun, Lu Wange
State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, China.
Department of Pharmacology, Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
iScience. 2023 Mar 25;26(4):106497. doi: 10.1016/j.isci.2023.106497. eCollection 2023 Apr 21.
To date, genome-wide association studies (GWAS) have revealed over 200 genetic risk loci associated with prostate cancer; yet, true disease-causing variants remain elusive. Identification of causal variants and their targets from association signals is complicated by high linkage disequilibrium and limited availability of functional genomics data for specific tissue/cell types. Here, we integrated statistical fine-mapping and functional annotation from prostate-specific epigenomic profiles, 3D genome features, and quantitative trait loci data to distinguish causal variants from associations and identify target genes. Our fine-mapping analysis yielded 3,395 likely causal variants, and multiscale functional annotation linked them to 487 target genes. We prioritized rs10486567 as a genome-wide top-ranked SNP and predicted as its target. Deletion of the rs10486567-associated enhancer in prostate cancer cells decreased their capacity for invasive migration. overexpression in enhancer-KO cell lines rescued defective invasive migration. Furthermore, we found that rs10486567 regulates through allele-specific long-range chromatin interaction.
迄今为止，全基因组关联研究（GWAS）已发现200多个与前列腺癌相关的遗传风险位点；然而，真正导致疾病的变异仍然难以捉摸。由于高度连锁不平衡以及特定组织/细胞类型的功能基因组学数据有限，从关联信号中识别因果变异及其靶点变得复杂。在此，我们整合了来自前列腺特异性表观基因组图谱、三维基因组特征和数量性状位点数据的统计精细定位和功能注释，以区分关联中的因果变异并识别靶基因。我们的精细定位分析产生了3395个可能的因果变异，多尺度功能注释将它们与487个靶基因联系起来。我们将rs10486567优先列为全基因组排名靠前的单核苷酸多态性（SNP），并预测 为其靶点。在前列腺癌细胞中删除与rs10486567相关的增强子会降低其侵袭性迁移能力。在增强子敲除细胞系中过表达 挽救了有缺陷的侵袭性迁移。此外，我们发现rs10486567通过等位基因特异性长程染色质相互作用调节 。
