Ancestry diversity in the genetic determinants of the human plasma proteome enhances identification of potential drug targets

作者：Alfred Pozarickij, Saredo Said, Kuang Lin, Sam Morris, Ahmed Edris, Andri Iona, Christiana Kartsonaki, Neil Wright, Pang Yao, Hannah Fry, Yiping Chen, Ling Yang, Huaidong Du, Derrick Bennett, Daniel Avery, Dan Schmidt, Jun Lv, Canqing Yu, Dianjianyi Sun, Pei Pei, Junshi Chen, Michael Hill, Richard Peto, Rory Collins, Robert Clarke, Liming Li, Iona Y. Millwood, Zhengming Chen, Robin Walters · 发表于：medRxiv · 年份：2023 · DOI：10.1101/2023.11.13.23298365 · 被引用次数：12 · 研究领域：Advanced Proteomics Techniques and Applications、Genetic Associations and Epidemiology、Ubiquitin and proteasome pathways

Abstract The proteome is fundamental to human biology and health but little is known about ancestral diversity of its genetic determinants. In GWAS of plasma levels of 2,923 proteins in 3,974 Chinese adults, we identified pQTLs for 1,784 proteins, including 1,312 cis -pQTLs for 1,264 proteins. Fine-mapping identified 3,475 credible sets for independent pQTLs, 36% of which were distinct from those identified in European adults as assessed by three different methods. In phenome-wide MR analyses, 59 disease associations were in strong LD (r 2 >0.95) with a cis -pQTL sentinel variant, including 26 with strong evidence of colocalisation (PP.H4>0.9) and 34 not identified in previous similar European studies. Evaluation of current drug development identified 8 confirmed therapeutic targets, 8 potential repurposing targets, and 19 potential novel targets (13 not previously reported in Europeans). The findings demonstrate the importance of extending proteogenomic studies to non-European ancestry populations to identify potential novel drug targets for major diseases.