Title | Nanoparticle enrichment mass-spectrometry proteomics identifies protein-altering variants for precise pQTL mapping. |
Publication Type | Journal Article |
Year of Publication | 2024 |
Authors | Suhre K, Venkataraman GRam, Guturu H, Halama A, Stephan N, Thareja G, Sarwath H, Motamedchaboki K, Donovan MKR, Siddiqui A, Batzoglou S, Schmidt F |
Journal | Nat Commun |
Volume | 15 |
Issue | 1 |
Pagination | 989 |
Date Published | 2024 Feb 02 |
ISSN | 2041-1723 |
Keywords | Humans, Mass Spectrometry, Mutant Proteins, Peptides, Proteins, Proteogenomics, Proteomics |
Abstract | 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. |
DOI | 10.1038/s41467-024-45233-y |
Alternate Journal | Nat Commun |
PubMed ID | 38307861 |
PubMed Central ID | PMC10837160 |
Grant List | NPRP11C-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) / |