Understanding genetic variation associated with differences in plasma protein levels can elucidate human disease mechanisms. Here, we demonstrate how untargeted nanoparticle enriched mass spectrometry (MS)-based plasma proteomics delivers quantitatively and qualitatively different insights compared to two affinity-based assays in a sample of ~1,400 British South Asians. We identify >1,200 significant locus-protein associations (p<8.7x10-12; n=895 cis-protein quantitative trait loci (pQTL)), half of which are novel. Cross-platform comparison demonstrated that multiple platforms are required to capture the full spectrum of pQTLs of blood proteins. We combine proteogenomic results with evidence from multiple biological domains to suggest a potential role of 21 proteins in the pathology of 44 diseases: e.g., an unreported role of IGLV3-21 in the development of Graves’ disease. Our results demonstrate the potential of MS-based blood proteomics in non-European ancestries for pQTL discovery and the need to consolidate proteogenomic evidence to confidently assign proteins to disease pathology.
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