Systematic disease-agnostic identification of therapeutically actionable targets using the genetics of human plasma proteins

Proteome-wide Mendelian randomization (MR) has emerged as a promising approach in uncovering novel therapeutic targets. However, genetic colocalization analysis has revealed that a third of MR associations lacked a shared causal signal between the protein and disease outcome, raising questions about the effectiveness of this approach. The impact of proteome-wide MR, stratified by cis-trans status, in the presence or absence of genetic colocalization, on therapeutic target identification remains largely unknown. In this study, we conducted genome-wide MR and cis/trans-genetic colocalization analyses using proteomic and complex trait genome-wide association studies. Using two different gold-standard datasets, we found that the enrichment of target-disease pairs supported by MR increased with more p-value stringent thresholds MR p-value, with the evidence of enrichment limited to colocalizing cis-MR associations. Using a phenome-wide proteogenetic colocalization approach, we identified 235 unique targets associated with 168 binary traits at high confidence (at colocalization posterior probability of shared signal > 0.8 and 5% FDR-corrected MR p-value). The majority of the target-trait pairs did not overlap with existing drug targets, highlighting opportunities to investigate novel therapeutic hypotheses. 42% of these non-overlapping target-trait pairs were supported by GWAS, interacting protein partners, animal models, and Mendelian disease evidence. Additionally, as previously reported, these high confidence target-trait pairs assisted with causal gene identification and helped uncover translationally informative novel biology, especially from trans-colocalizing signals, such as the association of lower intestinal alkaline phosphatase with a higher risk of inflammatory bowel disease in FUT2 non-secretors. Beyond target identification, we used MR of colocalizing signals to infer therapeutic directions and flag potential safety concerns. For example, we found that most genetically predicted therapeutic targets for inflammatory bowel disease could potentially worsen allergic disease phenotypes, except for TNFRSF6B where we observed directionally consistent associations for both phenotypes. Our results are publicly available (https://mk31.shinyapps.io/mr_app2/), enabling others to use proteogenomic evidence to appraise therapeutic targets. ### Competing Interest Statement MAK is now an employee of Variant Bio. JS is now an employee of Illumina. JM is an employee of Bristol-Myers Squibb. ESEM is an employee of Genmab. EM is an employee at Genomics PLC. MVH is an employee of 23andMe, CR, PS, SH and RAS are employees of GlaxoSmithKline. ### Funding Statement MAK, BA, JS, JH, AB, DO, MC, EMM, MG, ID were funded by Open Targets. This research was funded in part by a Wellcome Trust [Grant number 206194]. For the purpose of Open Access, the authors have applied a CC-BY public copyright license to any Author Accepted Manuscript version arising from this submission. ### 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: Summary data for both proteins and outcomes used for genetic analyses are publicly available from the GWAS catalog https://www.ebi.ac.uk/gwas/downloads/summary-statistics. 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 All data produced are available online at: https://ftp.ebi.ac.uk/pub/databases/opentargets/publishing/mendelian\_randomisation\_results/ [https://ftp.ebi.ac.uk/pub/databases/opentargets/publishing/mendelian\_randomisation\_results/][1] [1]: https://ftp.ebi.ac.uk/pub/databases/opentargets/publishing/mendelian_randomisation_results/