Harnessing Confounding and Genetic Pleiotropy to Identify Causes of Disease Through Proteomics and Mendelian Randomisation – ‘MR Fish’

We propose an extension of the Mendelian randomisation (MR) paradigm (‘MR-Fish’) in which the confounded disease association of an index protein (‘the bait’) is harnessed to identify the causal role of different proteins (‘the catch’) for the same disease. Using C-reactive protein (CRP) as the bait, cis -MR analyses refuted a causal relationship of CRP with a wide range of diseases that associate with CRP in observational studies, including type 2 diabetes (T2DM) and coronary heart disease (CHD), suggesting these associations are confounded. Using ‘MR-Fish’, and leveraging large-scale proteomics data, we find evidence of a causal relationship with multiple diseases for several proteins encoded by genes that are trans hits in genome wide association analysis of CRP. These include causal associations of IL6R and FTO with CHD and T2DM; as well as ZDHHC18 with several circulating blood lipid fractions. Among the proteins encoded by genes that are trans -for-CRP we identified 28 that are druggable. Our findings point to a general approach using MR analysis with proteomics data to identify causal pathways and therapeutic targets from non-causal observational associations of an index protein with a disease. ### Competing Interest Statement APK has acted as a paid consultant or lecturer to Abbvie, Aerie, Allergan, Google Health, Heidelberg Engineering, Novartis, Reichert, Santen, Thea and Topcon. AT report grants from Bayer and Novartis and personal fees from Abbvie, Allegro, Annexon, Apellis, Bayer, Heidelberg Engineering, Iveric Bio, Kanghong, Novartis, Oxurion, Roche/Genentech, Thea. CE reports personal fees from Heidelberg Engineering and Inozyme pharmaceuticals outside of the submitted work. ### Funding Statement This research was supported by the UCL NIHR Biomedical Research Centre, the UCL British Heart Foundation Research Accelerator, the UKRI-NIHR funded Multimorbidity Mechanisms and Therapeutics Research Collaborative (MR/V033867/1), and the National Institute for Health and Care Research (NIHR) Biomedical Research Centre based at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. ANW is supported by the Wellcome Trust (220558/Z/20/Z; 224390/Z/21/Z). KVS is supported by grants from Fight for Sight (1956A) and The Desmond Foundation. APK is supported by a UK Research and Innovation Future Leaders Fellowship, an Alcon Research Institute Young Investigator Award and a Lister Institute of Preventive Medicine Award. For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising. CE, and AT received a proportion of their financial support from the UK Department of Health through an award made by the National Institute for Health Research to Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology for a Biomedical Research Centre for Ophthalmology. CE receives a proportion of financial support to Moorfields Eye Hospital NHS Foundation Trust from the Lowy Medical Research Institute. AFS is supported by BHF grant PG/22/10989, the UCL BHF Research Accelerator AA/18/6/34223, and the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre. This work was funded by UK Research and Innovation (UKRI) under the UK government's Horizon Europe funding guarantee EP/Z000211/1. ADH is an NIHR Senior Investigator. ### 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: The study used ONLY openly available human data. Details of all source data are provided in the methods section and supplementary material. 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 in the present work are contained in the manuscript.