Synergistic insights into human health from aptamer- and antibody-based proteomic profiling

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.

Large-scale comparison of immunoassay- and aptamer-based plasma proteomics through genetics and disease

“…Five matching pairs of assays have a strong negative correlation (<-0.18) with those targeting PILRA having the strongest negative correlation (-0.32). As previously described, PILRA has a cis pQTL with opposite directions of effect on the Olink Explore and SomaScan v4 platforms 8 , a result that we also observe in our data (Arg78Gly; MAF=32%; Olink Explore p =7.9×10 -7823 , effect=-1.01 SD and SomaScan v4 p =1.0×10 -9045 , effect=1.31). We observe that the range of levels for matching assays was similar on the two platforms (IQR correlation 0.51, p =8.2×10 -81 ).…”

“…Direct comparison of the levels measured with matching assays on the two platforms gave a median correlation of 0.46, with a bimodal distribution with modes around 0 and 0.7. Similar correlation has been reported between proteins measured using Olink Target and SomaScan v4 8 , highlighting a clear difference between the platforms.…”

“…The Olink platform is offered either as 15 panels, each with 45 or 92 assays analyzed by qPCR (Olink Target), or as four panels of 384 assays analyzed by NGS (Olink Explore 1536). The Olink Target panels have been used both as a primary research instrument 3, 25 and for comparison with the SomaScan v4 platform 6, 8, 26 . The Olink Explore panels were released in 2020 and the only previous study using that platform 27 had a relatively small population size (n=101 individuals).…”

“…When normalizing the SomaScan v4 data, the final step of scaling the protein measurements to levels from reference samples was not performed 30 . This step has been shown to have a detrimental effect on the correlation between protein levels when comparing measurements made using the Olink Explore and SomaScan v4 platforms 8 .…”

“…Reciprocally, 64% (75% for cis and 61% for trans ) of the pQTLs identified using the Olink Target platform 3 were replicated using the SomaScan v4 platform (n=163 proteins) 2, 3 . A recent study 8 involved a larger number of proteins targeted by both platforms (n=871), but was limited by the low number of participants measured using the Olink Target platform (n=485).…”