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Abstract
Affinity-based proteomics has enabled scalable quantification of thousands of protein targets in blood enhancing biomarker discovery, understanding of disease mechanisms, and genetic evaluation of drug targets in humans through protein quantitative trait loci (pQTLs). Here, we integrate two partly complementary techniques—the aptamer-based SomaScan® v4 assay and the antibody-based Olink assays—to systematically assess phenotypic consequences of hundreds of pQTLs discovered for 871 protein targets across both platforms. We create a genetically anchored cross-platform proteome-phenome network comprising 547 protein–phenotype connections, 36.3% of which were only seen with one of the two platforms suggesting that both techniques capture distinct aspects of protein biology. We further highlight discordance of genetically predicted effect directions between assays, such as for PILRA and Alzheimer’s disease. Our results showcase the synergistic nature of these technologies to better understand and identify disease mechanisms and provide a benchmark for future cross-platform discoveries.
Highlights
Affinity-based proteomics has enabled scalable quantification of thousands of protein targets in blood enhancing biomarker discovery, understanding of disease mechanisms, and genetic evaluation of drug targets in humans through protein quantitative trait loci
We observed a lower fraction of shared genomic regions when comparing to publicly available Olink pQTLs8 with 39.1%, which was best explained by the presence of multiple nonspecific trans-pQTLs. Based on this assessment we identified the following factors to be associated with a higher likelihood of a distinct or platformspecific pQTL: (1) a lower observational correlation, (2) lower binding affinity of the SOMAmer reagent to the protein target, (3) linkage to a protein altering variant (PAV), (4) a high proportion of extreme values in SomaScan measurements and (5)
We further identified four pairs that were consistent across platforms once the effect of the lead cis-pQTL for the SomaScan assay has been taken into account, indicating recovery of biological plausible information by accounting for possible measurement artefacts
Summary
Affinity-based proteomics has enabled scalable quantification of thousands of protein targets in blood enhancing biomarker discovery, understanding of disease mechanisms, and genetic evaluation of drug targets in humans through protein quantitative trait loci (pQTLs). Modulating protein abundances or function represents the most common mode of action of drugs[10] and major pharmaceutical companies integrate protein quantitative trait loci (pQTLs) into their strategies to identify new drug targets or to repurpose existing drugs[11,12,13]. This has only been possible through the commercial development and application of scalable affinity-based proteomic techniques that can measure thousands of protein targets simultaneously. We show that protein–phenotype colocalisation seen with only one platform goes beyond missing target specificity and can be explained by alternative proteoforms induced by genetic variants altering the amino acid sequence of the protein and the effects of alternative splicing
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