Understanding the genetic architecture of the circulating proteome can help determine if a protein is causally linked to disease. Previous large-scale genome-wide association studies (GWAS) of proteins have mostly been conducted to pre-defined, targeted subsets of the proteome, and have often concentrated on low abundance proteins, many of which don’t exert their main function in serum. Mass spectrometry-based proteomics facilitates the study of high-abundance proteins and their isoforms, focussing on proteins active in blood. In 15,035 individuals from Generation Scotland, we performed GWAS of 439 highly abundant serum protein groups as identified and quantified by liquid chromatography tandem mass spectrometry. We identified 1,553 independent SNP signals for 398 proteins (PBonferroni < 1.2×10−10). Two-sample Mendelian Randomisation (MR) analyses were applied to test if the 398 proteins with significant SNP signals were causally associated with 79 common causes of morbidity and mortality. We report putative causal associations between 13 proteins and 17 outcomes including neuropsychiatric and cardiovascular conditions. Large scale genome-wide analyses of the high abundance proteome complement targeted approaches for the discovery of causal pathways of disease.

R.F.H. and R.E.M. act as scientific consultants for Optima Partners. R.E.M. is an advisor to the Epigenetic Clock Development Foundation. R.F.H. has received consultant fees from Illumina. All other authors declare no competing interests.

This research was funded in whole, or in part, by the Wellcome Trust [104036/Z/14/Z, 108890/Z/15/Z, 221890/Z/20/Z, 220857/Z/20/Z and 218493/Z/19/Z]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. GS received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006]. Genotyping of the GS samples was carried out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility, Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award "STratifying Resilience and Depression Longitudinally" (STRADL) Reference 104036/Z/14/Z). R.F.H. is supported by a British Heart Foundation Immediate Fellowship [FS/IPBSRF/22/27042]. C.H. is supported by an MRC Human Genetics Unit programme grant 'Quantitative traits in health and disease' [U. MC_UU_00007/10]. R.E.M. is supported by an Alzheimer's Society major project grant [AS-PG-19b-010]. H.M.S is a student on the Translational Neuroscience PhD programme funded by Wellcome [21843/Z/19/Z]. J.A.R. is a University of Edinburgh Clinical Academic Track PhD student, supported by the Wellcome Trust [319878/Z/24/Z]. A.D.C. is supported by a Medical Research Council PhD Studentship in Precision Medicine with funding from the Medical Research Council Doctoral Training Program and the University of Edinburgh College of Medicine and Veterinary Medicine.

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:

All components of Generation Scotland received ethical approval from the NHS Tayside Committee on Medical Research Ethics [REC Reference Number: 05/S1401/89]. Generation Scotland has also been granted Research Tissue Bank status by the East of Scotland Research Ethics Service [REC Reference Number: 20-ES-0021], providing generic ethical approval for a wide range of uses within medical research. All participants provided written informed consent.

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

According to the terms of consent for Generation Scotland participants, access to data must be reviewed by the Generation Scotland Access Committee. Applications should be made to accessgenerationscotland.org. All code associated with this manuscript is available open access at the following GitHub repository: https://github.com/marioni-group/Generation_Scotland_Protein_GWAS. GWAS summary statistics are available on request and will be submitted to the Edinburgh DataShare site and GWAS Catalog upon publication.