小柯机器人

英国剑桥大学Adam S. Butterworth和美国麻省总医院Krishna G. Aragam课题组合作取得一项新成果。经过不懈努力，他们通过超过100万参与者发现和系统表征了与冠状动脉疾病（CAD）相关的风险变异和基因。该项研究成果发表在2022年12月6日出版的《自然-遗传学》上。

研究人员针对冠状动脉疾病进行了一项全基因组关联研究（GWAS），共包括1,165,690名参与者，其中有181，522名参与者具有欧洲血统。研究人员检测到241个关联位点，其中包括30个新位点。使用日本人GWAS进行的跨祖先meta分析产生了38个额外的新位点。研究人员使用已知功能的精细映射对可能的因果变异进行了优先级排序，在95个可信集中产生了42个关联，其中少于5个变异。基于相似性的聚类揭示了早期发育过程、细胞周期信号传导和血管细胞迁移和增殖在CAD发病机制中的作用。

研究人员优先考虑了220个候选致病基因，其通过结合八种互补方法产生，其中123种由三种或更多方法支持。使用CRISPR-Cas9，研究人员利用实验验证了MYO9B中增强子的作用，该增强子似乎通过调节血管细胞运动来诱导CAD。该分析确定并系统地表征了与CAD相关的250个风险位点，并利用实验证明了CAD产生的可能因果机制。

据了解，已发现的与复杂疾病相关的遗传位点远超过了对疾病发病机制的了解。

附：英文原文

Title: Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants

Author: Aragam, Krishna G., Jiang, Tao, Goel, Anuj, Kanoni, Stavroula, Wolford, Brooke N., Atri, Deepak S., Weeks, Elle M., Wang, Minxian, Hindy, George, Zhou, Wei, Grace, Christopher, Roselli, Carolina, Marston, Nicholas A., Kamanu, Frederick K., Surakka, Ida, Venegas, Loreto Muoz, Sherliker, Paul, Koyama, Satoshi, Ishigaki, Kazuyoshi, svold, Bjrn O., Brown, Michael R., Brumpton, Ben, de Vries, Paul S., Giannakopoulou, Olga, Giardoglou, Panagiota, Gudbjartsson, Daniel F., Gldener, Ulrich, Haider, Syed M. Ijlal, Helgadottir, Anna, Ibrahim, Maysson, Kastrati, Adnan, Kessler, Thorsten, Kyriakou, Theodosios, Konopka, Tomasz, Li, Ling, Ma, Lijiang, Meitinger, Thomas, Mucha, Sren, Munz, Matthias, Murgia, Federico, Nielsen, Jonas B., Nthen, Markus M., Pang, Shichao, Reinberger, Tobias, Schnitzler, Gavin, Smedley, Damian, Thorleifsson, Gudmar, von Scheidt, Moritz, Ulirsch, Jacob C., Arnar, David O., Burtt, Nol P., Costanzo, Maria C., Flannick, Jason, Ito, Kaoru, Jang, Dong-Keun, Kamatani, Yoichiro, Khera, Amit V., Komuro, Issei, Kullo, Iftikhar J.

Issue&Volume: 2022-12-06

Abstract: The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR–Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.

DOI: 10.1038/s41588-022-01233-6

Source: https://www.nature.com/articles/s41588-022-01233-6

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
官方网址：https://www.nature.com/ng/
投稿链接：https://mts-ng.nature.com/cgi-bin/main.plex