Genome-wide analysis of 439 mass spectrometry-based proteomic profiles in a population of 15,035 Scottish individuals
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Anne Richmond Josephine A Robertson Hannah M Smith Robert F Hillary Aleksej Zelezniak Spyros Vernardis Aleksandra D Chybowska Arturas Grauslys Jure Mur Archie Campbell Camilla Drake Hannah Grant Poppy Adkin Matthew White Charles Brigden Christoph Messner David J Porteous Caroline Hayward Andrew M McIntosh Daniel L McCartney Markus Ralser Riccardo E MarioniThis article is a preprint. Preprints have not been peer-reviewed.
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Abstract
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.
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