A genome-wide association study of mass spectrometry proteomics using a nanoparticle enrichment platform

In this genome-wide association study, researchers applied the nanoparticle-enabled Seer Proteograph^® platform to quantify plasma proteins across ~1,600 individuals, enabling one of the most comprehensive MS-based pQTL analyses to date. By integrating Proteograph measurements with genetic data, the team identified 364 significant pQTLs, 102 of which replicated in an independent cohort of 325 participants of diverse ancestries.

The study revealed 35 previously unreported pQTLs — many located at disease-linked loci such as age-related macular degeneration, inflammatory bowel disease, lipid regulation, and immune disorders. MS-based profiling also exposed numerous cases where affinity-platform pQTLs likely reflected epitope-altering variants rather than true changes in protein abundance, with ~30% of sufficiently powered affinity pQTLs showing no peptide-level support in the MS data.

By resolving peptide-specific effects, distinguishing true abundance QTLs from epitope artifacts, and capturing proteins and isoforms not accessible to affinity assays, the Proteograph workflow substantially extended the accessible proteome for human pQTL discovery. The results highlight the value of nanoparticle-enabled mass spectrometry as a complementary and orthogonal approach to affinity proteomics—critical for validating causal mechanisms, improving biomarker interpretation, and expanding the landscape of genetically informed drug-target discovery.