Ancestry diversity in the genetic determinants of the human plasma proteome and associated new drug targets

Abstract

The proteome is fundamental to human biology and disease but little is known about ancestral diversity of its genetic determinants. In GWAS of plasma levels of 1,451 proteins in 3,974 Chinese adults, we identified pQTLs for 1,082 proteins, including 743 with at least one cis-pQTL. Fine-mapping defined credible sets for 3,336 independent pQTLs, of which 31% did not overlap with corresponding analyses in European adults. We assessed 777 sentinel cis-pQTLs in phenome-wide MR analyses using GWAS Catalog and identified Bonferroni-significant associations for 22 protein-disease pairs. Among 10 protein-disease pairs identified from East Asian-specific GWAS, four had evidence of colocalisation. Evaluation of current drug development confirmed indications for one protein target, identified potential repurposing for seven, and discovered nine potential novel targets, including GP2 for Type-2-diabetes. The findings demonstrate the importance of extending genome-wide plasma proteomic analyses to non-European ancestry populations to identify potential novel drug targets for major diseases.