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Cross-platform proteomics to advance genetic prioritisation strategies

By Maik Pietzner, Eleanor Wheeler, Julia Carrasco-Zanini, Nicola D. Kerrison, Erin Oerton, Mine Koprulu, Jian Luan, Aroon D. Hingorani, Steve A. Williams, Nicholas J Wareham, Claudia Langenberg

Posted 19 Mar 2021
bioRxiv DOI: 10.1101/2021.03.18.435919

Discovery of protein quantitative trait loci (pQTLs) has been enabled by affinity-based proteomic techniques and is increasingly used to guide genetically informed drug target evaluation. Large-scale proteomic data are now being created, but systematic, bidirectional assessment of platform differences is lacking, restricting clinical translation. We compared genetic, technical, and phenotypic determinants of 871 protein targets measured using both aptamer- (SomaScan(R) Platform v4) and antibody-based (Olink) assays in up to 10,708 individuals. Correlations coefficients for overlapping protein targets varied widely (median 0.38, IQR: 0.08-0.64). We found that 64% of pQTLs were shared across both platforms among all identified 608 cis- and 1,315 trans-pQTLs with sufficient power for replication, but with correlations of effect estimates being lower than previously reported (cis: 0.41, trans: 0.34). We identified technical, protein, and variant characteristics that contributed significantly to platform differences and found contradicting phenotypic associations attributable to those. We demonstrate how integrating phenomic and gene expression data improves genetic prioritisation strategies, including platform-specific pQTLs.

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