Seer Publishes Large Genome-Wide Study Confirming Importance of Mass Spectrometry Validation

Seer announced the publication in Nature Genetics of a large genome-wide association study that used the company's Proteograph Product Suite to measure proteins at peptide-level resolution and map their genetic determinants. The study, led by Karsten Suhre, PhD, of Weill Cornell Medicine-Qatar, with collaborators from Harvard Medical School/Brigham and Women's Hospital, Seer, and TruDiagnostic, provides the strongest evidence to date that mass spectrometry validation is essential for turning genomic signals into reliable drug targets and clinical biomarkers. Without mass spectrometry validation, as many as one-third of protein-gene associations reported by affinity-based assays do not replicate, highlighting the necessity of accuracy in proteogenomics. The analysis included ~1,600 blood samples representing multiple ethnic backgrounds. A discovery cohort of 1,260 and an independent replication cohort of 325 were profiled using Seer's Proteograph workflow. Across these samples, 5,753 proteins were detected, and 1,980 were quantified in at least 80 percent of participants. From these data, the researchers identified 364 protein quantitative trait loci genetic variants associated with protein abundance. Of these, 102 replicated in the independent cohort. 35 of the replicated signals were previously unreported, extending the catalog of genetic regulation of proteins. Affinity reagents have been used in proteomics to measure a predetermined panel of proteins in large cohorts and have generated thousands of reported pQTLs. But when protein-altering genetic variants change the binding site of affinity reagents, these methods can register erroneous signals as the binding strength of the affinity reagent to the protein is diminished. These so-called epitope effects can produce apparent associations between protein expression and genetic variants that do not represent true biology. By measuring proteins directly at the peptide level, the Proteograph's mass spectrometry approach made it possible to test whether a genetic variant truly altered protein expression, mitigating the confounding epitope effect. To contextualize the findings, the study compared mass spectrometry results with two of the largest affinity-based proteomics resources. The comparison revealed a clear pattern: pQTLs consistently reported across multiple affinity platforms were confirmed by mass spectrometry. Up to one-third of associations reported by a single affinity platform did not replicate when tested by mass spectrometry.