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

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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The CKB baseline survey and the first re-survey were supported by the Kadoorie Charitable Foundation in Hong Kong. The long-term follow-up and subsequent resurveys have been supported by Wellcome grants to Oxford University (212946/Z/18/Z, 202922/Z/16/Z, 104085/Z/14/Z, 088158/Z/09/Z) and grants from the National Natural Science Foundation of China (82192901, 82192904, 82192900) and from the National Key Research and Development Program of China (2016YFC0900500).The UK Medical Research Council (MC\_UU\_00017/1, MC\_UU\_12026/2, MC_U137686851), Cancer Research UK (C16077/A29186, C500/A16896) and the British Heart Foundation (CH/1996001/9454), provide core funding to the Clinical Trial Service Unit and Epidemiological Studies Unit at Oxford University for the project. The proteomic assays were supported by BHF (18/23/33512), Novo Nordisk and Olink. DNA extraction and genotyping were supported by GlaxoSmithKline and the UK Medical Research Council (MC-PC-13049, MC-PC-14135). Computation used the Oxford Biomedical Research Computing (BMRC) facility, a joint development between the Wellcome Centre for Human Genetics and the Big Data Institute supported by Health Data Research UK and the NIHR Oxford Biomedical Research Centre; the views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: N/A I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Full summary statistics data are available at [URL accessible on publication]. Other data presented in this study are included in this publication supplementary information.