Englander Institute for Precision Medicine

Nanoparticle enrichment mass-spectrometry proteomics identifies protein-altering variants for precise pQTL mapping.

TitleNanoparticle enrichment mass-spectrometry proteomics identifies protein-altering variants for precise pQTL mapping.
Publication TypeJournal Article
Year of Publication2024
AuthorsSuhre K, Venkataraman GRam, Guturu H, Halama A, Stephan N, Thareja G, Sarwath H, Motamedchaboki K, Donovan MKR, Siddiqui A, Batzoglou S, Schmidt F
JournalNat Commun
Date Published2024 Feb 02
KeywordsHumans, Mass Spectrometry, Mutant Proteins, Peptides, Proteins, Proteogenomics, Proteomics

Proteogenomics studies generate hypotheses on protein function and provide genetic evidence for drug target prioritization. Most previous work has been conducted using affinity-based proteomics approaches. These technologies face challenges, such as uncertainty regarding target identity, non-specific binding, and handling of variants that affect epitope affinity binding. Mass spectrometry-based proteomics can overcome some of these challenges. Here we report a pQTL study using the Proteograph™ Product Suite workflow (Seer, Inc.) where we quantify over 18,000 unique peptides from nearly 3000 proteins in more than 320 blood samples from a multi-ethnic cohort in a bottom-up, peptide-centric, mass spectrometry-based proteomics approach. We identify 184 protein-altering variants in 137 genes that are significantly associated with their corresponding variant peptides, confirming target specificity of co-associated affinity binders, identifying putatively causal cis-encoded proteins and providing experimental evidence for their presence in blood, including proteins that may be inaccessible to affinity-based proteomics.

Alternate JournalNat Commun
PubMed ID38307861
PubMed Central IDPMC10837160
Grant ListNPRP11C-0115-180010 / / Qatar National Research Fund (QNRF) /
Biomedical Research Program at Weill Cornell Medicine in Qatar / / Qatar Foundation (Qatar Foundation for Education, Science and Community Development) /

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