英国莱斯特大学Martin D. Tobin等研究人员合作发现，多祖先全基因组关联分析提高对影响肺功能和慢性阻塞性肺病风险的基因和途径的分辨率。2023年3月13日出版的《自然—遗传学》发表了这项成果。

在迄今为止最大的多祖先肺功能全基因组关联荟萃分析中，包括580869名参与者，研究人员确定了1020个独立的关联信号，牵涉到559个由系统性变异基因图谱框架的≥2个标准支持的基因。这些基因在29条途径中被富集。单个变体在不同的血统、年龄和吸烟群体中显示出异质性，而作为一个遗传风险分数，在不同的血统群体中显示出与慢性阻塞性肺病（COPD）的强烈关联。

研究人员对选定的相关变体以及性状和途径特定的遗传风险评分进行了表型组关联研究，以推断干预肺功能基础途径的可能后果。研究人员强调了新的潜在因果变体、基因、蛋白质和途径，包括那些现有药物的靶标。这些发现使人们更接近于了解肺功能和COPD的基础机制，并应为功能基因组学实验和可能的未来COPD治疗提供信息。

附：英文原文

Title: Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

Author: Shrine, Nick, Izquierdo, Abril G., Chen, Jing, Packer, Richard, Hall, Robert J., Guyatt, Anna L., Batini, Chiara, Thompson, Rebecca J., Pavuluri, Chandan, Malik, Vidhi, Hobbs, Brian D., Moll, Matthew, Kim, Wonji, Tal-Singer, Ruth, Bakke, Per, Fawcett, Katherine A., John, Catherine, Coley, Kayesha, Piga, Noemi Nicole, Pozarickij, Alfred, Lin, Kuang, Millwood, Iona Y., Chen, Zhengming, Li, Liming, Wijnant, Sara R. A., Lahousse, Lies, Brusselle, Guy, Uitterlinden, Andre G., Manichaikul, Ani, Oelsner, Elizabeth C., Rich, Stephen S., Barr, R. Graham, Kerr, Shona M., Vitart, Veronique, Brown, Michael R., Wielscher, Matthias, Imboden, Medea, Jeong, Ayoung, Bartz, Traci M., Gharib, Sina A., Flexeder, Claudia, Karrasch, Stefan, Gieger, Christian, Peters, Annette, Stubbe, Beate, Hu, Xiaowei, Ortega, Victor E., Meyers, Deborah A., Bleecker, Eugene R., Gabriel, Stacey B., Gupta, Namrata, Smith, Albert Vernon, Luan, Jianan, Zhao, Jing-Hua, Hansen, Ailin F., Langhammer, Arnulf, Willer, Cristen, Bhatta, Laxmi, Porteous, David, Smith, Blair H., Campbell, Archie, Sofer, Tamar, Lee, Jiwon, Daviglus, Martha L.

Issue&Volume: 2023-03-13

Abstract: Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.

DOI: 10.1038/s41588-023-01314-0

Source: https://www.nature.com/articles/s41588-023-01314-0